Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis

Summary of findings 1. Inhaled tobramycin (TNS) compared with placebo

Outcomes		*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (trials)	Certainty of the evidence (GRADE)	Comments
*Inhaled tobramycin (TNS) compared with placebo for eradicating Pseudomonas aeruginosa* in people with cystic fibrosis**
Patient or population: adults and children with cystic fibrosis and a positive microbiological isolate of Pseudomonas aeruginosa from a respiratory tract specimen Settings: outpatients Intervention: TNS Comparison: placebo
		Assumed risk	Corresponding risk
		Placebo	TNS
*Eradication of P aeruginosa* from the respiratory tract*: proportion with positive respiratory culture for P aeruginosa* Follow‐up: up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months (1 month)	787 per 1000	182 per 1000 (69 to 400 per 1000)	OR 0.06 (95% CI 0.02 to 0.18)	89 (3 RCTs)	⊕⊕⊝⊝ low^a,b	The included trials gave very different doses of TNS (80 mg or 300 mg 2 x daily).
	Follow‐up: 6 to 24 months after onset of treatment (12 months)	OR 0.02 (95% CI 0.00 to 0.67)		OR 0.02 (95% CI 0.00 to 0.67)	12 (1 RCT)	⊕⊝⊝⊝ very low^a,b,c	We were unable to calculate assumed and corresponding risk as all the participants in the placebo group had a positive respiratory culture at 12 months. Results of different time points and sensitivity analyses to account for missing data in 1 trial were variable, showing no consistent advantage to TNS over placebo.
FEV₁ Follow‐up: up to 2 years		There were no changes in spirometric pulmonary function during or after the treatment period.		NR	up to 22^d (1 RCT)	⊕⊝⊝⊝ very low^a,b,e	No numerical data were reported.
FVC Follow‐up: up to 2 years		There were no changes in spirometric pulmonary function during or after the treatment period.		NR	up to 22^d (1 RCT)	⊕⊝⊝⊝ very low^a,b,e	No numerical data were reported.
Growth and nutritional status: change in weight (kg) from baseline Follow‐up: up to 2 years		Outcome not reported at specified time point (see comments).					There was no difference in the mean change in weight from baseline between groups at 1 month (MD 0.20 kg, 95% CI ‐0.28 to 0.68) or 2 months (0.1 kg, 95% CI ‐0.38 to 0.58).
Frequency of infective pulmonary exacerbations: number of exacerbations per patient year		Outcome not reported.
Isolation of other micro‐organisms from the respiratory tract: number of positive cultures per patient year Follow‐up: up to 2 years		Outcome not reported at specified time point (see comments)					No numerical data were reported. At the 2‐month time point, there were no changes in the prevalence of other micro‐organisms, including multiresistant organisms, cultured from respiratory secretions.
Adverse effects of antibiotics: participants experiencing cough Follow‐up: up to 2 years		342 per 1000	283 per 1000 (49 to 750)	OR 0.76 (0.10 to 5.77)	72 (2 RCTs)	⊕⊝⊝⊝ very low^a,b,c	No other specific adverse events were reported. The trial reporting at 2 months found no difference between groups with regard to cough (OR 0.58, 95% CI 0.03 to 10.86), serum creatinine levels or auditory threshold at the 2‐month time point.
The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FEV₁: forced expiratory volume in one second; FVC: forced vital capacity; MD: mean difference; NA: not applicable; NR: not reported OR: odds ratio; P aeruginosa: Pseudomonas aeruginosa*; RCT: randomised controlled trial; TNS: inhaled tobramycin
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded once due to risk of bias; methodological information was limited and unclear in the included trials and there were concerns regarding incomplete outcome data, selective reporting and other biases due to the early termination of one trial. ^bDowngraded once due to applicability: the included trials recruited only children; results are not applicable to adults. ^cDowngraded once due to imprecision caused by very small sample size and wide CIs. ^dIn the included trial, 22 participants were randomised, but it is not clear if all participants contributed to this outcome. ^eDowngraded once due to imprecision: no numerical results available.

Summary of findings 2. Inhaled tobramycin (TNS) (28 days) compared with TNS (56 days)

Outcomes		*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
*Inhaled tobramycin (TNS) (28 days) compared with TNS (56 days) for eradicating Pseudomonas aeruginosa* in people with cystic fibrosis**
Patient or population: adults and children with cystic fibrosis and a positive microbiological isolate of P aeruginosa from a respiratory tract specimen Settings: outpatients Intervention: TNS (28 days) Comparison: TNS (56 days)
		Assumed risk	Corresponding risk
		TNS (56 days)	TNS (28 days)
*Eradication of P aeruginosa* from the respiratory tract:** time to next isolation of P aeruginosa from BAL, sputum or oropharyngeal cultures Follow‐up: up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months	Not reported at this time point
	Follow‐up: 6 to 24 months after onset of treatment	By 26.12 months, 50% of people in the 56‐day group can expect to have experienced a recurrence of P aeruginosa.	By 25.18 months, 50% of people in the 28‐day group can expect to have experienced a recurrence of P aeruginosa.	HR 0.81 (95% CI 0.37 to 1.76)	65^a (1 RCT)	⊕⊕⊝⊝ low^b,c
FEV₁: % predicted Follow‐up: 6 to 24 months (N.B. this trial reported at 27 months)		There were no major short‐ or long‐term changes in spirometric parameters were observed during the trial period.		NR	up to 88^a (1 RCT)	⊕⊝⊝⊝ very low^b,c,d	Changes in lung function were not reported separately for each treatment arm.
FVC: % predicted Follow‐up: 6 to 24 months (N.B. this trial reported at 27 months)		There were no major short‐ or long‐term changes in spirometric parameters were observed during the trial.		NR	up to 88^a (1 RCT)	⊕⊝⊝⊝ very low^b,c,d	Changes in lung function were not reported separately for each treatment arm.
Growth and nutritional status: weight, height and BMI Follow‐up: 6 to 24 months		No differences in weight, height or body mass index were reported.		NR	up to 88^a (1 RCT)	⊕⊝⊝⊝ very low^b,c,d	Numerical data were not reported or comparative results across the treatment groups.
Frequency of infective pulmonary exacerbations: number of exacerbations per patient year Follow‐up: 6 to 24 months (N.B. this trial reported at 27 months)		47 per 1000	9 per 1000 (0 to 188 per 1000)	OR 0.19 (95% CI 0.01 to 4.00)	77^a (1 RCT)	⊕⊝⊝⊝ very low^b,c,e
Isolation of other micro‐organisms from the respiratory tract: number of positive cultures per patient year Follow‐up: 6 to 24 months (N.B. this trial reported at 27 months)		There were no consistent trends reported in the isolation of non‐P aeruginosa organisms (one isolate only of Stenotrophomonas maltophilia, which was seen in the 28‐day arm).		NR	up to 88^a (1 RCT)	⊕⊝⊝⊝ very low^b,c,d	Numerical data were not reported, or comparative results across the treatment groups.
Adverse effects of antibiotics Follow‐up: 6 to 24 months (N.B. this trial reported at 27 months)		There were no differences between treatment groups in terms of any reported adverse events at any time point.		NA	up to 77^a (1 RCT)	⊕⊝⊝⊝ very low^b,c,f
The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BAL: bronchial lavage CI: confidence interval; FEV₁: forced expiratory volume in 1 second; FVC: forced vital capacity; HR: hazard ratio; NA: not applicable; NR: not reported OR: odds ratio; P aeruginosa: Pseudomonas aeruginosa*; RCT: randomised controlled trial; TNS: inhaled tobramycin.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aIn the included trial, 88 participants were randomised but not all participants contributed to all outcomes (unclear how many participants contributed to some outcomes). ^bDowngraded once due to risk of bias; methodological information was limited and unclear in the included trial and there were concerns of bias due to selective reporting of results and lack of blinding. ^cDowngraded once due to applicability: the included trials recruited only children; results are not applicable to adults. ^dDowngraded once due to imprecision: no numerical comparative results available. ^eDowngraded once due to imprecision: very wide CIs around the effect size ^fDowngraded once due to imprecision: some wide confidence intervals around effects sizes (small event rates) and a lot of adverse events analysed increasing the statistical chance of a spurious finding.

Summary of findings 3. Cycled inhaled tobramycin (TNS) compared to culture‐based TNS

Outcomes		*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
*Cycled inhaled tobramycin (TNS) compared to culture‐based TNS for eradicating Pseudomonas aeruginosa* in people with cystic fibrosis**
Patient or population: adults and children with cystic fibrosis and a positive microbiological isolate of P aeruginosa from a respiratory tract specimen Settings: outpatients Intervention: cycled TNS Comparison: culture‐based TNS
		Assumed risk	Corresponding risk
		Culture‐based inhaled tobramycin	Cycled inhaled tobramycin
*Eradication of P aeruginosa* from the respiratory tract:** proportion of participants with one or more isolates of P aeruginosa from the respiratory tract Follow‐up: up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months	Outcome not reported at this time point.
	Follow‐up: 6 to 24 months after onset of treatment	467 per 1000	228 per 1000 (145 to 383 per 1000)	OR 0.51 (95% CI 0.31 to 0.82)	298^a (1 RCT)	⊕⊕⊕⊝ moderate^b	The original trial report published age group–adjusted ORs, which are slightly different to the results of this review.
FEV₁: mean 70‐week % change in FEV₁ (% predicted) Follow‐up: 70 weeks		The mean 70‐week % change in FEV₁ (% predicted) was ‐1.61% in the culture‐based TNS group.	The mean 70‐week % change in FEV₁ (% predicted) was 2.38% higher (2% lower to 6.76% higher) in the cycle‐based TNS group.	NA	143^a (1 RCT)	⊕⊕⊝⊝ low^b,c
FVC		Outcome not reported.		NA	NA	NA
Growth and nutritional status: mean 70‐week change from baseline in weight (kg) and height (cm) Follow‐up: 70 weeks		The mean 70‐week change in weight (kg) in the culture‐based group was 3.9kg. Change in weight in the cycled group was 0.10kg higher (0.47 lower to 0.67 higher). The mean 70‐week change in height (cm) in the culture‐based group was 9.4cm. Change in height in the cycled group was 0.20cm lower (0.86 lower to 0.46 higher).		NA	304^a (1 RCT)	⊕⊕⊕⊝ moderate^b
Frequency of infective pulmonary exacerbations: proportion of participants with one or more pulmonary exacerbations (any severity) Follow‐up: 18 months		533 per 1000	400 per 1000 (256 to 624 per 1000)	OR 0.75 (95% 0.48 to 1.17)	304^a (1 RCT)	⊕⊕⊕⊝ moderate^b	There was also no difference between groups in terms of proportion of participants with 1 or more severe pulmonary exacerbation or in terms of time to pulmonary exacerbation (severe or any severity).
Isolation of other micro‐organisms from the respiratory tract: proportion of participants with new isolates of Stenotrophomonas maltophilia Follow‐up: 18 months		184 per 1000	217 per 1000 (118 to 390 per 1000)	OR 1.18 (95% CI 0.65 to 2.12)	279^a (1 RCT)	⊕⊕⊕⊝ moderate^b
Adverse effects of antibiotics: proportion of participants with one or more serious adverse events Follow‐up: 18 months		289 per 1000	246 per 1000 (147 to 405 per 1000)	OR 0.85 (95% 0.51 to 1.40)	304^a (1 RCT)	⊕⊕⊕⊝ moderate^b
The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FEV₁: forced expiratory volume in 1 second; FVC: forced vital capacity; NA: not applicable; NR: not reported OR: odds ratio; P aeruginosa: Pseudomonas aeruginosa*; RCT: randomised controlled trial; TNS: inhaled tobramycin.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aIn the included trial, 306 participants were randomised, 304 received treatment but not all participants contributed to all outcomes (unclear how many participants contributed to some outcomes, spirometry not performed in very young children (less than 4 years of age)). ^bDowngraded once due to applicability: the included trial recruited only children; results are not applicable to adults. Also, the included trial required participants to have been free of P aeruginosa for at least 2 years, so results may not be applicable to a wider population. ^cDowngraded once due to applicability: a large proportion of the randomised and treated participants (161 out of 304, 53%) did not contribute to this outcome.

Summary of findings 4. Ciprofloxacin compared to placebo added to cycled and culture‐based inhaled tobramycin (TNS) therapy

Outcomes		*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
*Ciprofloxacin compared to placebo added to cycled and culture‐based inhaled tobramycin (TNS) therapy for eradicating Pseudomonas aeruginosa* in people with cystic fibrosis**
Patient or population: adults and children with cystic fibrosis and a positive microbiological isolate of P aeruginosa from a respiratory tract specimen Settings: outpatients Intervention: ciprofloxacin added to cycled and culture‐based TNS therapy Comparison: placebo added to cycled and culture‐based TNS therapy
		Assumed risk	Corresponding risk
		Placebo added to cycled and culture‐based TNS therapy	Ciprofloxacin added to cycled and culture‐based TNS therapy
*Eradication of P aeruginosa* from the respiratory tract:** proportion of participants with one or more isolates of P aeruginosa from the respiratory tract Follow‐up: up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months	Outcome not reported at this time point.
	Follow‐up: 6 to 24 months after onset of treatment	362 per 1000	322 per 1000 (199 to 521 per 1000)	OR 0.89 (95% CI 0.55 to 1.44)	298^a (1 RCT)	⊕⊕⊕⊝ moderate^b	The original trial report published age group‐adjusted ORs, which are slightly different to the results of this review.
FEV₁: mean 70‐week % change in FEV₁ (% predicted) Follow‐up: 70 weeks		The mean 70‐week % change in FEV₁ (% predicted) was ‐1.85% in the placebo added to cycled and culture‐based TNS therapy group.	The mean 70‐week % change in FEV₁ (% predicted) was 3.02% higher (1.33% lower to 7.37% higher) in the ciprofloxacin added to cycled and culture‐based TNS therapy group.	NA	143^a (1 RCT)	⊕⊕⊝⊝ low^b,c
FVC		Outcome not reported.		NA	NA	NA
Growth and nutritional status: mean 70‐week change from baseline in weight (kg) and height (cm) Follow‐up: 70 weeks		The mean 70‐week change in weight (kg) in the placebo added to cycled and culture‐based therapy group was 4.10 kg. Change in weight in the cycled group was 0.30 kg lower (0.88 lower to 0.28 higher). The mean 70‐week change in height (cm) in the placebo added to cycled and culture‐based therapy group was 9.4 cm. Change in height in the cycled group was 0.20 cm lower (0.86 lower to 0.46 higher).		NA	304^a (1 RCT)	⊕⊕⊕⊝ moderate^b
Frequency of infective pulmonary exacerbations: proportion of participants with one or more pulmonary exacerbations (any severity) Follow‐up: 18 months		447 per 1000	666 per 1000 (425 to 1000)	OR 1.49 (95% CI 0.95 to 2.33)	304^a (1 RCT)	⊕⊕⊕⊝ moderate^b	There was also no difference between groups in the proportion of participants with 1 or more severe pulmonary exacerbations or in the time to pulmonary exacerbation (severe or any severity).
Isolation of other micro‐organisms from the respiratory tract: proportion of participants with new isolates of Stenotrophomonas maltophilia Follow‐up: 18 months		183 per 1000	220 per 1000 (121 to 395 per 1000)	OR 1.20 (95% CI 0.66 to 2.16)	279^a (1 RCT)	⊕⊕⊕⊝ moderate^b
Adverse effects of antibiotics: proportion of participants with one or more serious adverse event Follow‐up: 18 months		230 per 1000	354 per 1000 (214 to 591 per 1000)	OR 1.54 (95% CI 0.93 to 2.57)	304^a (1 RCT)	⊕⊕⊕⊝ moderate^b
The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FEV₁: forced expiratory volume in one second; FVC: forced vital capacity; NA: not applicable; NR: not reported; OR: odds ratio; P aeruginosa: Pseudomonas aeruginosa*; RCT: randomised controlled trial; TNS: inhaled tobramycin.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aIn the included trial, 306 participants were randomised, 304 received treatment but not all participants contributed to all outcomes (unclear how many participants contributed to some outcomes, spirometry not performed in very young children (less than 4 years of age)). ^bDowngraded once due to applicability: the included trial recruited only children; results are not applicable to adults. Also, the included trial required participants to have been free of P aeruginosa for at least 2 years, so results may not be applicable to a wider population. ^cDowngraded once due to applicability: a large proportion of the randomised and treated participants (161 out of 304, 53%) did not contribute to this outcome.

Summary of findings 5. Oral ciprofloxacin and inhaled colistin compared to inhaled tobramycin (TNS)

Outcomes		*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
*Oral ciprofloxacin and inhaled colistin compared to inhaled tobramycin for eradicating Pseudomonas aeruginosa* in people with cystic fibrosis**
Patient or population: adults and children with cystic fibrosis and a positive microbiological isolate of P aeruginosa from a respiratory tract specimen Settings: outpatients Intervention: oral ciprofloxacin and inhaled colistin Comparison: TNS
		Assumed risk	Corresponding risk
		TNS	Oral ciprofloxacin and inhaled colistin
*Eradication of P aeruginosa* from the respiratory tract:** proportion with positive respiratory culture for P aeruginosa Follow‐up: up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months	552 per 1000	346 per 1000	OR 0.43 (95% CI 0.15 to 1.23)	Up to 58^a (1 RCT)	⊕⊝⊝⊝ very low^b,c,d
	Follow‐up: 6 to 24 months after onset of treatment	458 per 1000	348 per 1000 (110 to 1000 per 1000)	OR 0.76 (95% CI 0.24 to 2.42)	Up to 58^a (1 RCT)	⊕⊝⊝⊝ very low^b,c,d
FEV₁: change from baseline (% predicted) Follow‐up: over 6 months and up to 24 months		Median change from baseline in FEV₁ (% predicted) for all the participants was ‐1%.		NR	Up to 58^a (1 RCT)	⊕⊝⊝⊝ very low^b,c,e	Changes in FEV₁ were not reported separately for each treatment arm.
FVC Follow‐up: NA		Outcome not reported.		NA	NA	NA
Growth and nutritional status: BMI and weight z score Follow‐up: 6 to 24 months		Both BMI z score and weight z score were reported not to have changed significantly for trial participants as a whole.		NR	Up to 58^a (1 RCT)	⊕⊝⊝⊝ very low^b,c,e	Numerical data were not reported for comparative results across the treatment groups.
Frequency of infective pulmonary exacerbations: number of exacerbations per patient year Follow‐up: over 6 months and up to 24 months		During the first 6 months of follow‐up, there was no difference between the 2 treatment arms in number of oral antibiotic treatment days.		NR	Up to 58^a (1 RCT)	⊕⊝⊝⊝ very low^b,c,e	These oral antibiotics were given for symptoms and not because of failed eradication. No numerical data were reported.
Isolation of other micro‐organisms from the respiratory tract: number of positive cultures per patient year Follow‐up: NA		Outcome not reported.		NA	NA	NA
Adverse effects of antibiotics: severe cough Follow‐up: over 6 months and up to 24 months		34 per 1000	11 per 1000 (0 to 280 per 1000)	OR 0.32 (95% CI 0.01 to 8.24)	Up to 58^a (1 RCT)	⊕⊝⊝⊝ very low^b,c,d	No other specific adverse events were reported.
The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BMI: body mass index; CI: confidence interval; FEV₁: forced expiratory volume in one second; FVC: forced vital capacity; NA: not applicable; NR: not reported OR: odds ratio; P aeruginosa: Pseudomonas aeruginosa*; RCT: randomised controlled trial; TNS: inhaled tobramycin.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aIn the included trial, 58 participants were randomised but not all participants contributed to all outcomes (unclear how many participants contributed to some outcomes). ^bDowngraded once due to risk of bias; methodological information was limited and unclear in the included trial and there were concerns of bias due to selective reporting of results. ^cDowngraded once due to applicability: the included trials recruited only children; results are not applicable to adults. ^dDowngraded once due to imprecision: very wide CIs around the effect size. ^eDowngraded once due to imprecision: no numerical comparative results available.

Summary of findings 6. Inhaled colistin plus oral ciprofloxacin compared to inhaled tobramycin (TNS) plus oral ciprofloxacin

Outcomes		*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
*Inhaled colistin plus oral ciprofloxacin compared to inhaled tobramycin (TNS) plus oral ciprofloxacin for eradicating Pseudomonas aeruginosa* in people with cystic fibrosis**
Patient or population: adults and children with cystic fibrosis and a positive microbiological isolate of P aeruginosa from a respiratory tract specimen Settings: outpatients Intervention: inhaled colistin plus oral ciprofloxacin Comparison: TNS plus oral ciprofloxacin
		Assumed risk	Corresponding risk
		TNS plus oral ciprofloxacin	Inhaled colistin plus oral ciprofloxacin
*Eradication of P aeruginosa* from the respiratory tract:** proportion with positive respiratory culture for P aeruginosa Follow‐up: up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months	347 per 1000	371 per 1000 (254 to 506	OR 1.11 (95% CI 0.64 to 1.92)	Up to 223^a (1 RCT)	⊕⊕⊝⊝ low^b,c
	Follow‐up: 6 to 24 months after onset of treatment (median 16 months)	315 per 1000	403 per 1000 (227 to 721 per 1000)	OR 1.28 (95% CI 0.72 to 2.29)	Up to 223^a (1 RCT)	⊕⊕⊝⊝ low^b,c
FEV₁: relative change in % predicted FEV₁ from baseline		Outcome not reported at specified time point.					After a mean time of 54 days there was no difference in mean relative change in FEV1 % predicted between groups, MD ‐2.40 (95% CI ‐5.89 to 1.09)
FVC Follow‐up: NA		Outcome not reported.
Growth and nutritional status Follow‐up: NA		Outcome not reported.
Frequency of infective pulmonary exacerbations: number of exacerbations per patient year Follow‐up: NA		Outcome not reported.
Isolation of other micro‐organisms from the respiratory tract: number of positive cultures per patient year Follow‐up: median 16 months		There were no differences during follow‐up between the two groups for isolation of: Stenotrophomonas maltophilia (OR 0.89 (95% CI 0.45 to 1.78)) ,Achromobacter xylosoxidans (OR 1.53 (95% CI 0.51 to 4.57))or Aspergillus species (OR 0.48 (95% CI 0.21 to 1.07)).		NA	205^a (1 RCT)	⊕⊕⊕⊝ moderate^b
Adverse effects of antibiotics: leading to trial discontinuation Follow‐up: median 16 months		21 out of 118 (18%) participants discontinued the trial early due to adverse events in the TNS plus oral ciprofloxacin group.	17 out of 105 (16%) participants discontinued the trial early due to adverse events in the inhaled colistin plus oral ciprofloxacin group.	NA	223 (1 RCT)	⊕⊕⊕⊝ moderate^b	Reasons for discontinuations included vomiting, photosensitivity, wheeze and pulmonary exacerbation.
The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FEV₁: forced expiratory volume in one second; FVC: forced vital capacity; NA: not applicable; NR: not reported OR: odds ratio; P aeruginosa: Pseudomonas aeruginosa*; RCT: randomised controlled trial; TNS: inhaled tobramycin.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aIn the included trial, 223 participants were randomised but not all participants contributed to all outcomes (unclear how many participants contributed to some outcomes, spirometry not performed in very young children). ^bDowngraded once due to risk of bias; methodological information was limited and unclear in the included trial and there were potential concerns of bias due to selective reporting of results and lack of blinding. ^cDowngraded once due to imprecision: wide CIs around the effect size.

Summary of findings 7. Inhaled tobramycin (TNS) plus oral azithromycin compared to TNS plus oral placebo

Outcomes		*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
*Inhaled tobramycin (TNS) plus oral azithromycin compared to TNS plus oral placebo for eradicating Pseudomonas aeruginosa* in people with cystic fibrosis**
Patient or population: children with cystic fibrosis and a new culture positive for P aeruginosa Settings: outpatients Intervention: TNS plus oral azithromycin Comparison: TNS plus oral placebo
		Assumed risk	Corresponding risk
		TNS plus placebo	TNS plus azithromycin
*Eradication of P aeruginosa* from the respiratory tract:** number of participants eradicated after three month treatment phase Follow‐up: up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months (3 months)	667 per 1000	674 per 1000 (500 to 900 per 1000)	RR 1.01 (0.75 to 1.35)	91 (1 RCT)	⊕⊕⊝⊝ low^a,b	This included participants who were positive for P aeruginosa at baseline and had a culture result available at the end of the first treatment quarter.
	Follow‐up: 6 to 24 months after onset of treatment	Outcome not reported at this time point.
FEV_1: mean change in FEV₁ % predicted Follow‐up: 18 months		There was no difference in the mean change in FEV₁ over the 18‐month period between groups, MD ‐1.71% (‐7.76 to 4.34).			132 (1 RCT)	⊕⊕⊝⊝ low^a,b	P = 0.384 Results taken directly from paper.
FVC: mean change in FVC % predicted Follow‐up: 18 months		There was no difference in the mean change in FVC over the 18‐month period between groups.				⊕⊕⊝⊝ low^a,b	No data are available for this outcome.
Growth and nutritional status: mean change in weight (kg) from baseline Follow‐up: 18 months		There was a slight improvement in weight in the azithromycin group compared to the placebo group, MD 1.27 (0.01 to ‐2.52)			221 (1 RCT)	⊕⊕⊕⊝ moderate^b	P = 0.046 Results taken directly from paper.
Frequency of infective pulmonary exacerbations: number of participants experiencing an exacerbation by the end of the study Follow‐up: 18 months		522 per 1000	392 per 1000 (292 to 522 per 1000)	RR 0.75 (0.56 to 1.00)	221 (1 RCT)	⊕⊕⊕⊝ moderate^b
Isolation of other micro‐organisms from the respiratory tract: number of participants with a positive result for other organisms. Follow‐up: 18 months		The emergence of other pathogens (including A xylosoxidans, B cepacia, H influenzae, S aureus, S maltophilia and NTM) was comparable between groups and numbers were low.			221 (1 RCT)	⊕⊕⊕⊝ moderate^b	The analysis included participants with a positive result who were negative at baseline.
Adverse effects of antibiotics: number of participants experiencing any adverse event Follow‐up: 18 months		883 per 1000	927 per 1000 (848 to 1000 per 1000)	RR 1.05 (0.96 to 1.14)	221 (1 RCT)	⊕⊕⊕⊝ moderate^b	There was no difference between groups in the occurrence of adverse events, including serious adverse events.
The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). A xylosoxidans: Achromobacter xylosoxidans;B cepacia: Burkholderia cepacia; CI: confidence interval; FEV₁: forced expiratory volume in 1 second; FVC: forced vital capacity; H influenzae: Haemophilus influenzae; MD: mean difference; NA: not applicable; NR: not reported; NTM: nontuberculous mycobacterium; OR: odds ratio; P aeruginosa: Pseudomonas aeruginosa; RCT: randomised controlled trial; RR: risk ratio; S aureus: Staphylococcus aureus; S maltophilia: Stenotrophomonas maltophilia;* TNS: inhaled tobramycin.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded once due to imprecision: small number of participants. ^bDowngraded once due to indirectness: the included trial recruited only children; results are not applicable to adults.

Summary of findings 8. Oral ciprofloxacin and inhaled colistin compared with no treatment

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
*Oral ciprofloxacin and inhaled colistincompared with no treatment for eradicating Pseudomonas aeruginosa* in people with cystic fibrosis**
Patient or population: adults and children with cystic fibrosis and a positive microbiological isolate of P aeruginosa from a respiratory tract specimen Settings: outpatients Intervention: oral ciprofloxacin and inhaled colistin Comparison: no treatment
	Assumed risk	Corresponding risk
	No treatment	Oral ciprofloxacin and inhaled colistin
*Eradication of P aeruginosa* from the respiratory tract**	Outcome not reported.
FEV₁	Outcome not reported.
FVC	Outcome not reported.
Growth and nutritional status	Outcome not reported.
Frequency of infective pulmonary exacerbations: number of exacerbations per patient year	Outcome not reported.
Isolation of other micro‐organisms from the respiratory tract: number of positive cultures per patient year	Outcome not reported.
Adverse effects of antibiotics Follow‐up: 27 months	No adverse effects were reported in either group.		NR	26 (1 RCT)	⊕⊝⊝⊝ very low^a,b,c	No numerical data were reported.
The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FEV₁: forced expiratory volume in one second; FVC: forced vital capacity; NA: not applicable; NR: not reported; P aeruginosa: Pseudomonas aeruginosa*; RCT: randomised controlled trial.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded once due to risk of bias; methodological information was limited and unclear in the included trial and there was a high risk of bias due to lack of blinding. ^bDowngraded once due to applicability: the included trial recruited only children; results are not applicable to adults. ^cDowngraded once due to imprecision: no numerical results available.

Summary of findings 9. 14 days inhaled AZLI plus 14 days placebo compared to 28 days inhaled AZLI

Outcomes		*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
*Inhaled AZLI 14 days followed by placebo 14 days compared with AZLI 28 days for eradicating Pseudomonas aeruginosa* in people with cystic fibrosis**
Patient or population: children and adolescents with cystic fibrosis Settings: not stated Intervention: 14 days of AZLI followed by 14 days of placebo Comparison: 28 days of AZLI
		Assumed risk	Corresponding risk
		AZLI 28 days	AZLI 14 days plus placebo 14 days
*Eradication of P aeruginosa* from the respiratory tract: proportion of participants with a negative culture for PA during the 28 days following treatment Follow‐up:** up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months (28 days)	The proportion of participants with a negative culture was 63.4% (51.97).	The proportion of participants with a negative culture was 7.50% lower in the AZLI 14 group than the AZLI 28 group (24.80% lower to 9.80% higher).	NA	139 (1 RCT)	⊕⊝⊝⊝ very low^a,b,c
	Follow‐up: 6 to 24 months after onset of treatment	Outcome not reported at this time point
FEV₁ % predicted		This outcome was not reported.
FVC % predicted		This outcome was not reported.
Growth and nutritional status		This outcome was not reported.
Frequency of infective pulmonary exacerbations		This outcome was not reported.
Isolation of other micro‐organisms from the respiratory tract		This outcome was not reported.
Adverse effects of antibiotics: number of participants reporting a serious adverse event		Outcome not reported at this time point.					Adverse events were reported at the 28‐day time point. There was no difference in serious adverse events between groups, RR 1.27 (95% CI 0.35 to 4.53)
The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AZLI: aztreonam lysine; CI: confidence interval; FEV₁: forced expiratory volume in 1 second; FVC: forced vital capacity; P aeruginosa: Pseudomonas aeruginosa*; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded once due to unclear risk of bias, particularly around randomisation and allocation concealment. The trial was described as randomised but no further details were given. ^bDowngraded once due to imprecision from a small number of participants. ^cDowngraded once due to indirectness as the trial was only conducted in children and adolescents. It is unclear whether the results would be reproducible in an adult population.

Summary of findings 10. Intravenous ceftazidime with tobramycin compared with oral ciprofloxacin

Outcomes		*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
*Intravenous ceftazidime with tobramycin compared with oral ciprofloxacin for eradicating Pseudomonas aeruginosa* in people with cystic fibrosis**
Patient or population: adults and children with cystic fibrosis and a positive microbiological isolate of Pseudomonas aeruginosa from a respiratory tract specimen Settings: outpatients Intervention: IV ceftazidime with tobramycin Comparison: oral ciprofloxacin
		Assumed risk	Corresponding risk
		Oral ciprofloxacin	IV ceftazidime
*Eradication of P aeruginosa* from the respiratory tract:** number of participants testing negative for P aeruginosa at 3 months and remaining free until 15 months Follow‐up: up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months	Outcome not reported at this time point					The primary outcome was the proportion of participants who were successfully eradicated at 3 months and remained free at 15 months.
	Follow‐up: 6 to 24 months after onset of treatment (15 months)	523 per 1000	439 per 1000 (340 to 570 per 1000)	RR 0.84 (0.65 to 1.09)	255 (1 RCT)	⊕⊕⊕⊕ high^a	30 participants were excluded from the primary analysis as they did not have a sample taken at 5 months. Further sensitivity analyses confirmed the same results.
FEV₁: mean FEV₁ % predicted Follow‐up: 15 months		FEV₁ % predicted was 84.11% after treatment with oral ciprofloxacin.	FEV₁ % predicted in the IV ceftazidime group was 2.08 % higher (0.81% lower to 4.97% higher).	N/A	285 (1 RCT)	⊕⊕⊕⊕ high^a
FVC: mean FVC % predicted Follow‐up: 15 months		FVC % predicted was 90.94% after treatment with oral ciprofloxacin.	FVC % predicted was 3.14% higher in the IV ceftazidime group (0.31% higher to 5.97% higher).	N/A	285 (1 RCT)	⊕⊕⊕⊕ high^a
Growth and nutritional status: weight‐for‐age z score Follow‐up: 15 months		Weight‐for‐age z score was 0.13 in the oral ciprofloxacin group.	Weight‐for‐age z score was 0.02 lower in the IV ceftazidime group (0.15 lower to 0.11 higher).	N/A	285 (1 RCT)	⊕⊕⊕⊕ high^a
Frequency of infective pulmonary exacerbations: number of participants experiencing an exacerbation Follow‐up: 15 months		356 per 1000	278 per 1000 (196 to 392 per 1000)	RR 0.78 (0.55 to 1.10)	285 (1 RCT)	⊕⊕⊕⊕ high^a
Isolation of other micro‐organisms from the respiratory tract: number of participants isolating other micro‐organisms within the 15‐month follow‐up. Follow‐up: 15 months		There was no difference between treatments in the number of participants who grew other organisms: MRSA (RR 2.07, 95% CI 0.39 to 11.14); B cepacia (RR 0.51, 95% CI 0.10 to 2.76); Candida spp (RR 1.04, 95% CI 0.78 to 1.40); and Aspergillus spp (RR 0.72, 95% CI 0.38 to 1.37).			285 (1 RCT)	⊕⊕⊕⊕ high^a
Adverse effects of antibiotics: Follow‐up: 15 months		There was no difference in serious adverse events (RR 0.97, 95% CI 0.43 to 2.16) or non‐serious adverse events (RR 0.97, 95% CI 0.75 to 1.24) between groups, except for URTI where there were fewer incidences in the oral antibiotic treatment group (RR 6.37, 95% CI 1.44 to 28.21).			285 (1 RCT)	⊕⊕⊕⊝ moderate^b
The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). B cepacia: Burkholderia cepacia; CI: confidence interval; FEV₁: forced expiratory volume in one second; FVC: forced vital capacity; IV: intravenous; MD: mean difference; MRSA: methicillin‐resistant Staphylococcus aureus; N/A: not applicable; NR: not reported; P aeruginosa: Pseudomonas aeruginosa*; RCT: randomised controlled trial; RR: risk ratio; URTI: upper respiratory tract infection.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aWe have not downgraded the evidence for this outcome despite the trial being open‐label. It is unlikely that knowledge of the allocation would influence the results for this outcome. ^bDowngraded once due to risk of bias; this was an open‐label trial, and it is unclear whether knowledge of treatment arm may have affected this outcome.

Background

Description of the condition

Cystic fibrosis (CF) is the most common life‐limiting, autosomal recessively inherited disease in populations of Northern European descent (Farrell 2018). Although this is a multisystem disease, the primary cause of death in CF is respiratory failure resulting from chronic pulmonary infection (FitzSimmons 1993). The most frequent cause of chronic pulmonary infection beyond infancy in people with CF is Pseudomonas aeruginosa and, once established, appears to be permanent in the majority of cases (Fitzsimmons 1996). A number of definitions have been used for chronic P aeruginosa infection in CF.

The presence of P aeruginosa in monthly specimens for six successive months or the development of precipitating antibodies to P aeruginosa, or both (Valerius 1991).
The culture of P aeruginosa from the sputum or respiratory secretions, on two or more occasions extending over six months or a shorter period if accompanied by a sustained rise of anti‐pseudomonal antibodies (UK CF Trust 2004).
The isolation of P aeruginosa in more than 50% of months over a 12‐month period (Lee 2003) ‐ the second and subsequent positive specimens in the same month do not count. Conversely, eradication is defined as all monthly specimens negative for P aeruginosa over 12 months.
Three or more isolates of P aeruginosa in a 12‐month period (UK CF Registry 2012).

We have used the first definition in this systematic review.

The age‐specific prevalence of P aeruginosa in preschool children is under 5% (UK CF Trust 2021). Some authors have suggested that the use of prophylactic anti‐staphylococcal antibiotic therapy in early childhood may predispose to chronic P aeruginosa infection (Ratjen 2001b; Stutman 2002). However, this effect was not seen in a systematic review of prophylactic anti‐staphylococcal antibiotic use including over 400 participants (Rosenfeld 2020).

In children who are too young to expectorate, cough swabs or oropharyngeal swabs are the only respiratory specimens which can be easily obtained. These do not reliably predict the presence of P aeruginosa in the lower respiratory tract (Armstrong 1996; Rosenfeld 1999), whereas flexible fibreoptic bronchoscopy with bronchoalveolar lavage (BAL) may detect positive P aeruginosa in children with negative cough swabs or oropharyngeal swabs (Douglas 2009; Hilliard 2007). Sputum cultures have been shown to accurately reflect lower respiratory tract organisms in expectorating children and adults (Iacocca 1963; Thomassen 1984). Around a third of people with CF have chronic infection with P aeruginosa by their mid‐20s (UK CF Trust 2021), although prior to chronic infection P aeruginosa is often isolated intermittently from respiratory tract specimens. This may represent transient colonies of P aeruginosa within the lower respiratory tract, or alternatively it may reflect the difficulties in accurately detecting P aeruginosa in the lungs of young people with CF (Burns 2001). The quantity and type of P aeruginosa present in the lower respiratory tract changes as infection becomes established. It is known that P aeruginosa has two major phenotypes ‐ mucoid and non‐mucoid. Following first isolation there is a progressive increase in the density of P aeruginosa colonies in the lower respiratory tract (Rosenfeld 2001). Initial isolates often show a non‐mucoid phenotype; however, as infection progresses a mucoid phenotype may prevail and will be more difficult to eradicate. Douglas has reported a relatively high prevalence (18.2%) of mucoid P aeruginosa at first isolation in infants diagnosed with CF during newborn screening, speculating that the notion of transformation from non‐mucoid to mucoid phenotype under environmental pressure may be inaccurate in young children (Douglas 2009). It has been reported that P aeruginosa provokes an inflammatory response of the lower respiratory tract (Muhlebach 1999), and there is a marked step‐up in this inflammatory response as the number of P aeruginosa colonies increases (Armstrong 1996).

The presence of P aeruginosa in respiratory secretions is a major predictor of mortality in children with CF (Emerson 2002). Individuals with CF infected with P aeruginosa also suffer greater morbidity with a more rapid deterioration in lung function (Emerson 2002; Pamukcu 1995), and a more rapid decline in chest radiograph score (Kosorok 2001), poor growth, reduced quality of life (QoL), increased hospitalisation and increased need for antibiotic treatment (Ballman 1998; Nixon 2001; Winnie 1991). Some studies suggest there is a temporal relationship between the onset of chronic infection and increased morbidity (Abman 1991; Hudson 1993; Kosorok 2001; Parad 1999), whilst others do not support these findings (Kerem 1990; Rosenfeld 2001). On balance, there seems to be good evidence from well‐designed non‐experimental studies that clinical state deteriorates after first isolation of P aeruginosa.

There is evidence that, when P aeruginosa is cleared from respiratory secretions, it is not simply suppressed because, when infection recurs, this is with a genetically distinct organism in most cases (Munck 2001). However, a recent study from a Danish‐based group found that by using omics‐based tracking in nearly half (43%) of those treated, recurrence was due to the same clone type, even after a period of negative cultures for more than six months. This suggests that P aeruginosa persistence and suppression may be more common despite apparent eradication (Bartell 2021).

Description of the intervention

Several strategies exist to treat early infection with P aeruginosa, and include the use of the inhaled antibiotics such as colistin and tobramycin (Littlewood 1985; Ratjen 2001a), oral quinolones such as ciprofloxacin (Taccetti 2005), and intravenous (IV) antibiotics usually consisting of combination of an aminoglycoside with a beta‐lactam (Döring 2000; Douglas 2009).

As well as antibiotic treatment of P aeruginosa given at the time of first isolation, other strategies have the potential to prevent or delay infection of the respiratory tract. These include avoidance of contact with people who carry P aeruginosa (UK CF Trust 2004), and the development of vaccines against P aeruginosa (Johansen 2015). Most CF centres advocate frequent microbiological surveillance with attempts to eradicate P aeruginosa when it first appears in the lung (Döring 2000).

How the intervention might work

Uncontrolled series have indicated that a variety of anti‐pseudomonal antibiotics either singly (Littlewood 1985; Ratjen 2001a), or in combination (Vazquez 1993), at first isolation may delay the onset of chronic infection. A trial using historical controls suggested that oral ciprofloxacin and nebulised colistin are effective in delaying or preventing chronic infection (Frederiksen 1997). An uncontrolled pilot study of IV therapy suggested that IV treatment alone was less effective in delaying the onset of chronic infection (Steinkamp 1989). There is also evidence supporting eradication therapy from long‐term observational studies of chronic infection with P aeruginosa in CF clinics, such as the study reported by Lee 2004.

Why it is important to do this review

There are multiple different eradication regimens that have been described using different anti‐pseudomonal antibiotics in different combinations of IV, oral or nebulised (or both), and with varying doses and duration of therapy (Lee 2009). Additionally, given the expense of chronic anti‐pseudomonal suppressive therapy, there is a clear rationale for early eradication from a cost‐effectiveness perspective and this is supported by observational data (Taccetti 2005); however, there has not been any formal evaluation of cost‐effectiveness to date.

This is an update of a Cochrane Review first published in 2003, and regularly updated since (Wood 2003; Wood 2006; Langton‐Hewer 2009; Langton‐Hewer 2014; Langton‐Hewer 2017).

Objectives

Does giving antibiotics for P aeruginosa infection in people with CF at the time of new isolation improve clinical outcomes (e.g. mortality, quality of life and morbidity), eradicate P aeruginosa infection, and delay the onset of chronic infection, but without adverse effects compared to usual treatment or an alternative antibiotic regimen? We also assessed cost‐effectiveness.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) were eligible for inclusion in this review.

Types of participants

We included people with CF of all ages and disease severity, diagnosed clinically and by sweat or genetic testing (or both), with a first ever positive microbiological isolate of P aeruginosa from a respiratory tract specimen. We also included trials where the participants had been proven to be free of P aeruginosa for at least six months before a new isolation and should not have currently been receiving Pseudomonas‐suppressing treatment (such as daily inhaled antibiotic therapy). Participants should have been enrolled into a trial within six months (post hoc change ‐ previously not more than two months) from isolation of P aeruginosa. In a further post hoc change, we also altered our eligibility criteria to allow trials where all participants received some eradication therapy before randomisation (see Differences between protocol and review).

Types of interventions

We included combinations of inhaled, oral or IV antibiotics with the aim of eradicating first pulmonary isolates of P aeruginosa compared with placebo or usual treatment (or both), or other combinations of inhaled, oral or IV antibiotics.

Note on terminology: the following synonyms and acronyms are used for inhaled tobramycin in the literature: tobramycin solution for inhalation (TSI); tobramycin inhalation solution (TIS); and tobramycin nebuliser solution (TNS). We will use the term TNS in this manuscript for consistency (except where other terminology is included in the title of an included trial, or when we quote directly from the trial).

Types of outcome measures

We planned to assess the following outcome measures.

Primary outcomes

Eradication of P aeruginosa from the respiratory tract as defined by
1. clearance of P aeruginosa from BAL, sputum or oropharyngeal cultures at 1, 2, 3, 6, 12 and 24 months after commencement of therapy
2. time to next isolation of P aeruginosa from BAL, sputum or oropharyngeal cultures

Secondary outcomes

Mortality
QoL assessment measured using standardised and validated QoL scores (e.g. Cystic Fibrosis Questionnaire ‐ Revised (CFQ‐R) (Quittner 2009))
Spirometric lung function (% predicted values for age, sex and height)
1. forced expiratory volume in one second (FEV₁)
2. forced vital capacity (FVC)
3. forced expiratory flow between 25% and 75% of vital capacity (FEF_25-75)
Growth and nutritional status as measured by
1. weight (kg)
2. height (children) (cm)
3. body mass index (BMI) or z score
Frequency of respiratory exacerbations as defined by
1. frequency of infective pulmonary exacerbations expressed as the number of exacerbations per patient year
2. time to next course of IV antibiotics from commencement of therapy
3. days in hospital expressed as days in hospital per patient year
4. days of antibiotic usage expressed as days of antibiotic usage per patient year
Isolation of other micro‐organisms from the respiratory tract (e.g. Staphylococcus aureus, non‐tuberculous mycobacteria (NTM)) expressed as the number of positive cultures per patient year (where available, we planned to describe the microbiology detection method in view of the differences in sensitivity and specificity of oropharyngeal, sputum and BAL samples for bacteriology and mycology)
Adverse effects of antibiotics, e.g. renal or auditory impairment and hypersensitivity reactions

Additional outcomes which have arisen during the review

Time to chronic infection (as defined above in Description of the condition)
Clinical and radiological scores
Cost‐effectiveness (we planned to compare trials looking at cost‐effectiveness, where possible)

Search methods for identification of studies

We searched for all relevant published and unpublished trials without restrictions on language, year or publication status.

Electronic searches

Relevant trials were identified from the Group's Cystic Fibrosis Trials Register using the terms: antibiotics AND (pseudomonas aeruginosa OR mixed infections) AND (eradication OR unknown).

The Cystic Fibrosis Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of the Cochrane Library), weekly searches of MEDLINE, a search of Embase to 1995 and the prospective handsearching of two journals ‐ Pediatric Pulmonology and the Journal of Cystic Fibrosis. Unpublished work has been identified by searching the abstract books of three major CF conferences: the International Cystic Fibrosis Conference; the European Cystic Fibrosis Conference and the North American Cystic Fibrosis Conference. For full details of all searching activities for the Trials Register, please see the relevant sections of the Group's website.

Date of the most recent search of the Group's trials register: 24 March 2022.

We also searched the following trial registries.

US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov; searched 6 April 2022).
World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (trialsearch.who.int/; searched 6 April 2022).
International Standard Randomised Controlled Trial Number (ISRCTN) Registry (www.isrctn.com/; searched 6 April 2022).

For details of our search strategies, please see Appendix 1.

Searching other resources

We checked the reference lists of included trials and any systematic reviews identified from the searches for any relevant trials we may have missed.

Data collection and analysis

Selection of studies

For the original review, two authors (DW, AS) independently selected the trials to be included in the review. From Issue 3, 2009 of the Cochrane Library, two authors (SLH, AS) selected the trials to be included in the review. For the current 2023 update, three authors (SS, NR, AY) screened and selected trials. Where there was disagreement on the suitability of a trial for inclusion in the review, we reached a consensus by discussion.

Data extraction and management

For the original review, two authors (DW, AS) extracted data; from 2009 to 2017 this was undertaken by SLH and AS. For the 2023 update, three different authors (SS, NR, AY) undertook data extraction since the original review authors are authors on one of the newly included trials (TORPEDO 2020). Each author independently extracted data using standard data acquisition forms. Where there was disagreement on the data extracted, we reached a consensus by discussion.

We planned to group outcome data into those measured at up to one month, greater than one month to three months, greater than three months to six months and greater than six months to 12 months, then annually thereafter. In addition, we previously stated that if trials recorded outcome data at other time periods, we would also consider examining these data. Some trials reported data at two months for some outcomes, and we have included these data within the review. The Taccetti 2012 trial reported cumulative data at six months and final follow‐up data at a median of 16 months (range 12 to 28 months); we have included both time points in our analysis. The Treggiari 2011 trial presented cumulative data for pulmonary exacerbations and isolates of P aeruginosa for the 70‐week follow‐up period, and we have reported and analysed these data in this review.

Assessment of risk of bias in included studies

For earlier versions of this review, in order to assess the risk of bias, each author independently assessed the methodological quality of each trial, based on the method described by Schulz 1995. For the current update, each author independently assessed the risk of bias using the tool recommended by Cochrane (Higgins 2017). We judged the risks of bias as high, unclear or low for the domains of:

sequence generation;
allocation concealment;
blinding (risk of bias increased as the level of blinding decreased);
incomplete outcome data (the risk of bias increased if any withdrawals were not adequately described and reasons for withdrawals given, or if the withdrawals were not equal across groups);
selective outcome reporting (bias increased if stated outcome measures were only partially reported or not reported at all);
other potential sources of bias.

Where there was disagreement on the quality and risk of bias of a trial, we reached a consensus by discussion.

Measures of treatment effect

For binary outcome measures (eradication of P aeruginosa, mortality, isolation of micro‐organisms and adverse effects), in order to allow an intention‐to‐treat analysis, the authors sought data on the number of participants with each outcome event, by allocated treatment group, irrespective of compliance and whether the participant was later thought to be ineligible or otherwise excluded from treatment or follow‐up. We calculated a pooled estimate of the treatment effect for each outcome across trials ‐ the odds ratio (OR) or the ratio of the odds of an outcome among treatment allocated participants to the corresponding odds among controls, with 95% confidence intervals (CIs). We presented binary data on clearance of P aeruginosa from BAL, sputum or oropharyngeal cultures and occurrence of chronic infection with P aeruginosa at multiple time points. We calculated the OR at each time point separately, thus ignoring the correlation between time points.

For continuous outcomes (QoL, lung function, weight, height, BMI, number of respiratory exacerbations, days in hospital, days of antibiotic use, clinical and radiological scores), in order to allow an intention‐to‐treat analysis, we sought outcome data by allocated treated group, irrespective of compliance and whether the participant was later thought to be ineligible or otherwise excluded from treatment or follow‐up. We recorded either mean change from baseline for each group or mean post‐treatment or intervention values and standard deviation (SD). We calculated a pooled estimate of treatment effect by calculating the mean difference (MD) with 95% CIs.

In this version of the review, we entered time‐to‐event data into the meta‐analysis using the log hazard ratio. This was possible for the outcome 'time to pulmonary exacerbation' (severe or any), in the comparison of cycled versus culture‐based therapy (Analysis 3.5; Analysis 3.7) and ciprofloxacin versus placebo (Analysis 4.5; Analysis 4.7). We used the generic inverse variance (GIV) to analyse the data for time to next isolation of P aeruginosa from the Ratjen 2010 trial. For future updates of this review, for time‐to‐event data, such as time to next P aeruginosa infection or time to chronic infection, we will attempt to obtain individual participant data (IPD). We will use the IPD to provide estimates of the log hazard ratio and its standard error (SE), and plan to combine time‐to‐event data from trials in a meta‐analysis.

We have reported longitudinal data as individual time points. We realise that this method ignores any correlation between the participants; however, we have been unable to analyse these data using more appropriate methods as we do not have the correlation coefficient for these data. If in the future, we are able to obtain the correlation coefficient, we will analyse these data more appropriately.

Where trials included a health economic component, we have reported results directly from the trial paper. If more data are available in a future update, we will conduct a full or partial economic evaluation of interventions to eradicate P aeruginosa.

Unit of analysis issues

Cross‐over trials were not eligible for inclusion in this review.

The natural history of infection with P aeruginosa in CF comprises an initial infection with the organism, usually in planktonic form, followed by chronic infection (in which the P aeruginosa frequently exists in the mucoid state). In the planktonic form, antibiotics can eradicate the organism; however, persistent infection is associated with biofilm growth and adaptive evolution mediated by genetic variation. The development of mucoidy, hypermutability and the acquisition of mutational antibiotic resistance are important factors associated with persistent infection and are associated with increased difficulty in eradication (Ciofu 2012).

If active treatment was compared to a placebo in a cross‐over trial, given the progression of infections due to of P aeruginosa, the group receiving the active treatment after placebo would be at a disadvantage compared with those receiving active treatment first. During placebo treatment, P aeruginosa may form a biofilm, so it would not be able to be eradicated during the active treatment phase. Hence, a cross‐over trial is an inappropriate design, and we have not included cross‐over trials in this review.

Dealing with missing data

In trials where outcome data were unavailable for randomised participants, we performed an available‐case analysis. This available‐case analysis included data on only those participants whose results are known, using as a denominator the total number of people who completed the trial for the particular outcome in question.

When data were incomplete, we imputed the missing data to provide best‐case and worst‐case scenarios, in order to show the range of possible results for the combined analysis (Analysis 1.4; Analysis 1.5). The best‐case scenario analysis is based on the assumption that all the missing data points represented beneficial clinical outcomes, whereas the worst‐case analysis assumes that all missing data points had a negative clinical outcome.

Assessment of heterogeneity

For future updates of this review, if we are able to combine data from different trials, we will test for heterogeneity using the I² statistic (Deeks 2022). We will consider values of I² indicative of levels of heterogeneity as follows.

0% to 40%: might not be important
30% to 60%: may represent moderate heterogeneity
50% to 90%: may represent substantial heterogeneity
75% to 100%: considerable heterogeneity

We accept that the importance of the observed value of I² depends firstly on the magnitude and direction of effects and secondly on strength of evidence for heterogeneity (e.g. P value from the Chi² test, or a CI for I²). In a future version of this review (with more trials included in the meta‐analysis of individual treatment comparisons), if we find evidence of at least substantial clinical heterogeneity (as defined above) in the included trials, we will perform a random‐effects analysis.

Assessment of reporting biases

We sought evidence of reporting bias by comparison of the reported outcomes with those listed in the trial's methodological description. Where important outcomes have not been identified, we have requested the original trial protocol from the authors.

Data synthesis

We have analysed the data using a fixed‐effect model. In future updates of this review, if we find evidence of at least substantial clinical heterogeneity (as defined above) in the included trials, we plan to perform a random‐effects analysis.

Subgroup analysis and investigation of heterogeneity

If we identify a moderate degree of heterogeneity or higher in a future update (Deeks 2022), and are able to combine a sufficient number of trials (at least 10), then we will investigate this with subgroup analyses. We plan to categorise participants, if possible, as P aeruginosa‐free and P aeruginosa‐naive according to the definition by Lee 2003. We will analyse these subgroups separately.

Sensitivity analysis

We also planned to test the robustness of our results with the following sensitivity analyses:

trials where participants receive treatment within three months of isolation of P aeruginosa versus those where the interval is between three and 12 months; to do this we would need to include studies where eradication treatment was started up to 12 months after initial isolation of P aeruginosa;
trials with high risk of bias versus low risk of bias for generation of allocation sequence;
trials with a high risk of bias versus a low risk of bias for concealment of allocation;
multicentre versus single‐centre trials.

We were not able to carry out sensitivity analyses as there were not enough trials to combine in a meta‐analysis.

Summary of findings and assessment of the certainty of the evidence

In a post hoc change in line with current Cochrane guidance, at the 2023 update, we added a summary of findings table for each comparison presented in the review. We selected the following seven outcomes to report (chosen based on relevance to clinicians and consumers):

eradication of P aeruginosa from the respiratory tract;
FEV₁ (% predicted);
FVC (% predicted);
weight (kg);
frequency of infective pulmonary exacerbations;
isolation of other micro‐organisms from the respiratory tract; and
adverse effects of antibiotics, e.g. renal or auditory impairment and hypersensitivity reactions.

For eradication of P aeruginosa from the respiratory tract, we reported data at 'up to six months' and also 'six months up to 24 months' from treatment onset.

For all other outcomes we reported at 'six months up to 24 months' from treatment onset. One trial reported spirometry at 27 months, and we have included these data in the summary of findings tables for reference (Ratjen 2010).

We determined the certainty of the evidence using the GRADE approach; and downgraded evidence in the presence of a high risk of bias in at least one domain, indirectness of the evidence, unexplained heterogeneity or inconsistency, imprecision of results, high probability of publication bias. We downgraded evidence by one level if they considered the limitation to be serious and by two levels if very serious.

Results

Description of studies

Please see the characteristics tables for further information (Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification; Characteristics of ongoing studies). We present the flow of references through assessment stages in Figure 1.

Figure 1

Study flow diagram.

Results of the search

Our search identified a total of 70 trials; none of these were cross‐over trials; although one trial did offer an option for participants to cross over to the alternative treatment arm after the initial 28‐day parallel trial (EARLY 2019). Of these 70 trials, 11 met our inclusion criteria (ALPINE2 2017; EARLY 2019; Gibson 2003; OPTIMIZE 2018; Proesmans 2013; Ratjen 2010; Taccetti 2012; TORPEDO 2020; Treggiari 2011; Valerius 1991; Wiesemann 1998). We had previously listed three of these trials in the review as ongoing, but as these have now been completed we have included them; two have been published as full papers (EARLY 2019; TORPEDO 2020), and the third has results posted on the trial registration website (ALPINE2 2017). Three trials are still ongoing, and we will include data from these trials in a future update of this review, once the results have been published (EUCTR2007‐003868‐22‐FR; EUCTR2011‐006171‐19‐IT; EUCTR2015‐003881‐96‐IT). We excluded 55 trials (see below), and one trial is listed under Studies awaiting classification (Noah 2010). We have contacted the investigators of this trial for further information to allow us to include or exclude it at a future update.

Included studies

The 11 included trials enrolled a total of 1449 participants (ALPINE2 2017; EARLY 2019; Gibson 2003; OPTIMIZE 2018; Proesmans 2013; Ratjen 2010; Taccetti 2012; TORPEDO 2020; Treggiari 2011; Valerius 1991; Wiesemann 1998).

Trial characteristics

All 11 included trials were randomised controlled trials (RCTs) of parallel design. One trial reported stratification for age and participating centre (Gibson 2003), another trial reported stratification by age and FEV₁ values as an expression of illness severity (Taccetti 2012); one trial stratified by age (OPTIMIZE 2018); one trial stratified by participating centre (TORPEDO 2020); the remaining seven trials did not use stratification (ALPINE2 2017; EARLY 2019; Proesmans 2013; Ratjen 2010; Treggiari 2011; Valerius 1991; Wiesemann 1998). In one trial the first treatment phase was a double‐blind parallel trial, which was followed by an optional phase where participants could choose to switch to the alternative treatment arm; we have only included the initial parallel phase in our review (EARLY 2019). Five trials stated that they were double‐blind (ALPINE2 2017; EARLY 2019; Gibson 2003; OPTIMIZE 2018; Wiesemann 1998); the Treggiari 2011 trial used placebo to blind for ciprofloxacin, but not for TNS (described in the paper as TSI); the other trials could not be blinded due to differing treatment regimens (Proesmans 2013; Ratjen 2010; Taccetti 2012; TORPEDO 2020; Valerius 1991).

Nine trials were multicentre (ALPINE2 2017; EARLY 2019; Gibson 2003; OPTIMIZE 2018; Ratjen 2010; Taccetti 2012; TORPEDO 2020; Treggiari 2011; Wiesemann 1998), and the remaining two were single‐centre trials (Proesmans 2013; Valerius 1991). Six trials were based in Europe (Proesmans 2013; Ratjen 2010; Taccetti 2012; TORPEDO 2020; Valerius 1991; Wiesemann 1998), and three took place in North America (Gibson 2003; OPTIMIZE 2018; Treggiari 2011). One trial was carried out in Europe, Israel and North America (ALPINE2 2017), and the EARLY 2019 trial was carried out across nine countries in Europe, North America, North Africa and Russia.

The duration of the trials varied and ranged from 28 days (EARLY 2019; Gibson 2003) to 27 months (Valerius 1991). The duration of the intervention varied greatly, from three weeks (Valerius 1991) to 18 months (OPTIMIZE 2018).

Participants

The number of participants in each trial ranged from 21 to 304 and were as follows: 304 in Treggiari 2011; 286 in TORPEDO 2020; 223 in Taccetti 2012; 221 in OPTIMIZE 2018; 149 in ALPINE2 2017; 88 in Ratjen 2010; 58 in Proesmans 2013; 51 in EARLY 2019; 26 in Valerius 1991; 22 in Wiesemann 1998; and 21 in Gibson 2003. The Gibson trial reported that the planned sample size was 98 participants, but randomisation was stopped after an early interim analysis by the Data Monitoring Committee was undertaken due to poor accrual. This analysis showed a statistically significant treatment effect and so the trial was stopped (Gibson 2003).

Only three trials recruited adult participants; Taccetti 2012 recruited participants aged from one to 35 years, and the Ratjen 2010 trial included participants over six months of age. The TORPEDO trial included adults and children, but only 15 of the 286 participants were over 18 years (TORPEDO 2020). Two trials were restricted to younger children: three months to six years (EARLY 2019; Gibson 2003); one to children aged two to nine years (Valerius 1991); and one to 12 years (Treggiari 2011); the final four trials included children between the ages of one month and 18 years (ALPINE2 2017; OPTIMIZE 2018; Proesmans 2013; Wiesemann 1998).

All 11 trials had approximately equal numbers of males and females.

All 11 trials specified that participants had to have microbiological evidence of recent onset of airway infection with P aeruginosa. However, the interval allowed between isolation of P aeruginosa and randomisation to treatment varied greatly, from three weeks (TORPEDO 2020) to as long as six months (Treggiari 2011). Two trials additionally specified that individuals with raised titres to anti‐pseudomonal antibodies were excluded from the trial (Ratjen 2010; Wiesemann 1998). Other data from the EPIC trial (Treggiari 2011) have shown that raised antibodies to P aeruginosa (anti‐alkaline protease and anti‐exotoxin A) are associated with an increased risk of recurrence in the 60 weeks following eradication treatment (Anstead 2013). Trials excluding participants with raised antibodies might therefore be expected to achieve higher eradication rates.

Intervention

Trials used various combinations of intravenous ceftazidime and tobramycin, inhaled tobramycin, azithromycin, inhaled colistin, oral ciprofloxacin, inhaled aztreonam, placebo and no treatment. Four trials were placebo‐controlled (EARLY 2019; Gibson 2003; OPTIMIZE 2018; Wiesemann 1998); one trial compared 14 days of treatment versus 28 days of the same treatment (ALPINE2 2017); one trial compared active treatment to no treatment (Valerius 1991); and four open‐label trials compared different active treatments (Proesmans 2013; Ratjen 2010; Taccetti 2012; TORPEDO 2020). The design of the EPIC trial was complex, with randomisation to cycled treatment with TNS or culture‐based treatment and further randomisation to additional oral ciprofloxacin or placebo (Treggiari 2011).

Three trials compared tobramycin to placebo (EARLY 2019; Gibson 2003; Wiesemann 1998). Two trials used TNS (known as TOBI^® and now marketed by Novartis) at a dose of 300 mg twice‐daily for 28 days (EARLY 2019; Gibson 2003); the third trial used aerosolised tobramycin parenteral preparation (Eli Lilly, Bad Homburg, Germany) at a dose of 80 mg twice‐daily for 12 months (Wiesemann 1998).

Ratjen 2010 also used TNS and evaluated a short (28 days) versus a longer (56 days) course of treatment.

Participants in the Treggiari 2011 trial were randomised to one of four arms; they received either cycles of four weeks of treatment with nebulised TNS (with or without ciprofloxacin) in every 12‐week period or TNS (with or without ciprofloxacin) only when respiratory culture was positive for P aeruginosa. All trial participants had an initial 28‐day course of TNS, with an additional 28 days given if the participant remained positive after initial treatment. Ciprofloxacin or placebo was not given with the second course of TNS, and follow‐up was for 18 months from randomisation and first treatment with TNS (Treggiari 2011).

One trial compared 14 days of inhaled aztreonam lysine (AZLI) followed by 14 days of an inhaled placebo with 28 days of AZLI (ALPINE2 2017).

One trial compared the addition of oral azithromycin to inhaled tobramycin with an oral placebo in addition to inhaled tobramycin (OPTIMIZE 2018).

Three trials evaluated oral ciprofloxacin in combination with inhaled colistin (Proesmans 2013; Taccetti 2012; Valerius 1991). Proesmans 2013 compared oral ciprofloxacin 30 mg/kg/day in combination with colistin 2 million units (MU) twice daily for three months to TNS 300 mg twice daily for 28 days. In the Taccetti 2012 trial, both arms received oral ciprofloxacin 30 mg/kg/day for 28 days, additionally one group received 28 days of inhaled colistin while the second group received 28 days TNS. Valerius 1991 compared ciprofloxacin 250 mg plus colistin 1 MU to ciprofloxacin 750 mg plus colistin 1 MU, both given twice daily for three weeks for initial and any subsequent isolate of P aeruginosa, to no treatment.

The TORPEDO trial compared 10 days of IV ceftazidime and tobramycin with three months of oral ciprofloxacin (TORPEDO 2020), both groups also receiving three months of inhaled colistin.

Outcome measures

The most widely used primary outcome measure was eradication of P aeruginosa from respiratory secretions, though definitions of eradication differ considerably between trials. In the Gibson 2003 trial, the primary outcome was the change in P aeruginosa density in BAL from baseline to 28 days. However, the trial also looked at eradication at 28 days, and defined eradication as a density of P aeruginosa in BAL of less than 20 colony forming units (CFU). The EARLY 2019 trial reported negative respiratory culture at 28 days. Proesmans 2013 defined eradication as a negative culture result for P aeruginosa (from sputum, cough swab or BAL) at 28 days or three months (depending on which intervention the participant received). Both trials based successful eradication on a single specimen (Gibson 2003; Proesmans 2013). In contrast, Taccetti 2012 used a more stringent definition of eradication as per guidance published by the UK CF Trust of three negative cultures in a six‐month period (UK CF Trust 2004). Ratjen 2010 used the median time to recurrence of any strain of P aeruginosa during a 27‐month follow‐up period. In the oldest trial, the primary outcome measure was time to chronic infection with P aeruginosa, defined as the presence of P aeruginosa in monthly sputum samples for six consecutive months or the development of precipitating serum antibodies against P aeruginosa or both (see Description of the condition for other definitions of chronic infection) (Valerius 1991). There were two primary outcomes in the Treggiari 2011 trial, time to pulmonary exacerbation requiring IV antibiotics and proportion of P aeruginosa positive cultures over the 18‐month trial period. The TORPEDO 2020 trial looked at eradication from respiratory samples at three months from commencing treatment and also at remaining free of infection at 15 months.

The primary outcome in the OPTIMIZE 2018 trial was time to a protocol‐defined exacerbation, but investigators reported the number of participants with negative respiratory culture for P aeruginosa after the first quarter of therapy. One of the secondary outcomes was time to P aeruginosa recurrence after the first treatment period (OPTIMIZE 2018). Similarly, a second trial reported on the percentage of participants with negative cultures over the 28 days of treatment and then reported time to recurrence over a 108‐week follow‐up period (ALPINE2 2017).

Other measured outcomes included less severe pulmonary exacerbations, Pseudomonas antibody levels, lung function, nutritional status, modified Shwachman score and monitoring for adverse clinical and microbiological effects.

Excluded studies

We excluded 55 trials from our analysis for a number of reasons. Three trials were not randomised (Gibson 2007; Postnikov 2000; Schelstraete 2010) and one trial was an observational study (Ballman 1998). Four trials did not have a control group (Heinzl 2002; Littlewood 1985; Ratjen 2001a; Steinkamp 1989), and a further five used a historical control group (Frederiksen 1997; Griese 2002; Kenny 2009; Taccetti 2005; Vazquez 1993). A total of 25 trials involved participants with chronic P aeruginosa infection (Bustamante 2014; Clancy 2013; Coates 2011; Elborn 2015; Flume 2015a; Flume 2015b; Flume 2016; Geller 2011; Goss 2009; Konstan 2010; Konstan 2011; Konstan 2015; Latzin 2008; Lenoir 2007; Mazurek 2012; Oermann 2009; Postnikov 2007; Prayle 2013; Ramsey 1999; Retsch‐Bogart 2008; Retsch‐Bogart 2009; Steinkamp 2007; Stockmann 2015; Trapnell 2012; Wainwright 2011b). Two trials were designed to evaluate a diagnostic technique for P aeruginosa (Brett 1992; Wainwright 2011a). A further five trials evaluated symptomatic rather than eradication treatment (Church 1997; Frost 2021; Hansen 2015; Herrmann 2017; Schaad 1997), and one was of a prophylactic antibiotic regimen to prevent infection with P aeruginosa (Tramper‐Stranders 2009). Seven trials looked at pharmacokinetics and drug tolerability (Alothman 2002; Alothman 2005; Geller 2007; Rietschel 2009; Ruddy 2013; Schuster 2013; Stass 2013), and the final two trials looked at antibiotic sinonasal nebulisation aiming to eradicate from the sinuses only (Di Cicco 2014; Mainz 2014).

Studies awaiting assessment

One single‐centre, randomised, prospective trial is currently awaiting assessment (Noah 2010). The trial enrolled children with CF (stable disease) and positive surveillance cultures for P aeruginosa. Investigators compared twice‐daily nebulised tobramycin (300 mg) for four weeks or intravenous ceftazidime with tobramycin for two weeks at standard weight‐adjusted doses. The primary efficacy endpoint was change in BAL fluid percentage neutrophils from the most affected lobe at bronchoscopy. Secondary outcomes included change in BAL fluid differential cell counts, cytokines and bacterial quantity.

Eight out of 15 participants had a first ever isolate of P aeruginosa and their data are eligible to be included in this review; however, these outcome data are not published separately, and we have contacted the lead author for them.

Ongoing studies

Three trials are listed as ongoing (EUCTR2007‐003868‐22‐FR; EUCTR2011‐006171‐19‐IT; EUCTR2015‐003881‐96‐IT).

The three ongoing trials are only available as trial registration documents; all three trials include children and adults with CF and new identification of P aeruginosa infection, with the objective of eradicating P aeruginosa (EUCTR2007‐003868‐22‐FR; EUCTR2011‐006171‐19‐IT; EUCTR2015‐003881‐96‐IT).

One trial compares inhaled tobramycin to placebo (EUCTR2007‐003868‐22‐FR); a second trial compares two different antibiotic protocols (oral ciprofloxacin and inhaled promixin versus oral ciprofloxacin and inhaled tobramycin (EUCTR2011‐006171‐19‐IT); and the third trial compares inhaled aztreonam for 14 days versus inhaled aztreonam for 29 days (EUCTR2015‐003881‐96‐IT).

The primary outcome in all three trials is eradication, with secondary outcomes including safety, time to recurrence, lung function, growth indices, number of exacerbations and antibiotic use (EUCTR2007‐003868‐22‐FR; EUCTR2011‐006171‐19‐IT; EUCTR2015‐003881‐96‐IT).

Risk of bias in included studies

Please see further information in the risk of bias sections of the tables (Characteristics of included studies) and the graphical risk of bias summary (Figure 2).

Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Generation of allocation sequence

All 11 trials were described as RCTs; six trials did not state the method of sequence generation, hence we judged these trials to have an unclear risk of bias (ALPINE2 2017; EARLY 2019; Gibson 2003; Proesmans 2013; Ratjen 2010; Valerius 1991). We judged the remaining five trials to have a low risk of bias (OPTIMIZE 2018; Taccetti 2012; TORPEDO 2020; Treggiari 2011; Wiesemann 1998). One trial used an adaptive randomisation (dynamic allocation based on minimisation) method to ensure equal representation in each study arm for each age strata (OPTIMIZE 2018). In a second trial, investigators describe a balanced randomisation sequence that was created using statistical software using permuted blocks of size 10 (Taccetti 2012). The TORPEDO 2020 trial employed a secure web‐based randomisation system, which was controlled centrally, and randomisation lists were generated by a statistician who had no involvement in the trial. Treggiari 2011 employed a computerised random number generator to assign treatments within permuted blocks of 12. In the Wiesemann 1998 trial, the allocation sequence was generated using a coin flip; there is no information as to who was responsible for the coin flip or what controls were in place to ensure validity of the result of the coin flip; however we have still judged this to have a low risk of bias.

Allocation concealment

Seven trials did not report how allocation was concealed, and we judged these to have an unclear risk of bias (ALPINE2 2017; EARLY 2019; Gibson 2003; Proesmans 2013; Ratjen 2010; Valerius 1991; Wiesemann 1998). We deemed the remaining four trials to have adequate allocation concealment and rated them to be at low risk of bias for this domain (OPTIMIZE 2018; Taccetti 2012; TORPEDO 2020; Treggiari 2011). In the Taccetti 2012 trial, the staff involved in randomisation and in treatment assignments were "kept separate". In the Treggiari 2011 trial, randomisation was remote and so allocation was concealed.

Blinding

Five trials were reported as double‐blind RCTs, and we graded these as having a low risk of performance and detection bias (ALPINE2 2017; EARLY 2019; Gibson 2003; OPTIMIZE 2018; Wiesemann 1998). The protocol for ALPINE2 2017 stated that the participants and the investigators were blinded. Gibson 2003 did not provide any details in the published paper regarding who was blinded or the method of blinding. However, in response to a request for further information, Dr Gibson confirmed that drugs and placebo were sufficiently masked that neither participants nor clinicians were able to differentiate between them (Gibson 2003). The OPTIMIZE 2018 trial reported that treatment arms were unknown to participants, parents, and site research staff, and we graded this as low risk of bias. Wiesemann 1998 reported that participants were blinded as the placebo inhalation had a similar taste to the treatment inhalation; while it is not clear whether the clinicians administering the treatment were blinded to treatment allocation, we still judged this trial to have a low risk of bias.

We judged two trials to have an unclear risk of bias (TORPEDO 2020; Treggiari 2011). The TORPEDO 2020 trial was open‐label and whilst objective outcomes (eradication of P aeruginosa) are unlikely to have been at risk of bias through lack of blinding, this may not be the case for subjective outcomes such as QoL and treatment burden. In the Treggiari 2011 trial, the oral ciprofloxacin treatment was blinded, but the TSI was open‐label.

We judged the remaining four trials to have a high risk of bias as they did not utilise blinding (Proesmans 2013; Ratjen 2010; Taccetti 2012; Valerius 1991). The Proesmans 2013 trial compared an inhaled intervention to a combination of inhaled and oral treatment, so blinding of participants and clinicians was not possible; there is no information available as to whether the outcome assessors were blinded. The Ratjen 2010 trial was open‐label, comparing 28 or 56 days of nebulised therapy, and made no attempt at blinding. The Taccetti 2012 trial was also open‐label, comparing 28 days of inhaled colistin with 28 days of TNS; both groups also receiving 28 days of oral ciprofloxacin. Valerius 1991 compared a combination of inhaled and oral treatment to no treatment, so again blinding of participants and clinicians was not possible, and no information is available regarding the outcome assessors.

Incomplete outcome data

We judged seven trials to have a low risk of bias (Gibson 2003; Proesmans 2013; Ratjen 2010; Taccetti 2012; TORPEDO 2020; Treggiari 2011; Valerius 1991). Four trials were analysed on an intention‐to‐treat basis; all four reported data on all participants who were randomised (Gibson 2003; Proesmans 2013; Taccetti 2012; Valerius 1991). In the Ratjen 2010 trial, 65 of the 88 randomised participants were included in the primary outcome (time to recurrence of P aeruginosa). A total of 52 participants were prematurely withdrawn from the trial, but these were approximately evenly distributed across the two treatment groups and reasons were given for each withdrawal. In the Treggiari 2011 trial only two of 306 randomised participants were excluded from the analysis (because they did not receive treatment). In the TORPEDO 2020 trial, 30 of 286 randomised participants, in whom P aeruginosa was not detected after completion of eradication, were excluded from analysis of the primary outcome because they did not have a sample taken at around 15 months. Data were missing from one participant.

We judged three trials to have an unclear risk of bias (ALPINE2 2017; OPTIMIZE 2018; Wiesemann 1998). More than 15% of the participants in ALPINE2 2017 did not complete the study and no information was given on any intention‐to‐treat analysis (ALPINE2 2017). In OPTIMIZE 2018, 33 participants withdrew from the trial (11.8% in the treatment group and 18% in the placebo group); although an intention‐to‐treat analysis included all the participants, it is unclear how the dropout rate has affected the results (OPTIMIZE 2018). Wiesemann 1998 reported that five participants withdrew from the trial after randomisation and only presented baseline data at trial entry for these participants; to date, we have been unable to obtain further outcome data. We therefore analysed this trial on an available‐case basis.

We judged one trial to be at high risk of bias from attrition bias as 35% of the participants discontinued the study after being randomised, five from the intervention group and 13 from the placebo arm (EARLY 2019). The main reason for discontinuing was due to P aeruginosa positivity.

Selective reporting

It is current practice for newer trials to publish a protocol, but we have not been able to locate a published protocol for the Taccetti 2012 trial and have therefore judged this trial to have an unclear risk of bias. We judged three trials to have a high risk of bias (Proesmans 2013; Ratjen 2010; Wiesemann 1998). Although a protocol for the Proesmans 2013 trial was available online, and we were able to confirm from the full paper that all outcomes from the protocol were measured, the paper did not provide actual data for BMI z score, weight z score or frequency of exacerbations and simply reported that none of these changed significantly for trial participants. Ratjen 2010 reported that there were no major short‐term (at three months) or long‐term (at 27 months) changes in spirometry, but did not record the figures for either of the two groups. In addition, only summary statements and no numerical data were provided for weight, height or BMI (Ratjen 2010). Wiesemann 1998 reported no change in spirometric pulmonary function during or after the treatment period, but again reported no data.

We judged seven trials to have a low risk of bias from selective reporting (ALPINE2 2017; EARLY 2019; Gibson 2003; OPTIMIZE 2018; TORPEDO 2020; Treggiari 2011; Valerius 1991). The trial protocol for the EPIC trial was published as a separate paper; primary and secondary outcome measures were clearly described in the protocol and data on all of these outcomes were presented in either the main paper, related papers or in the online supplement (Treggiari 2011). We have compared the 'Methods' sections of the reports from two trials with the 'Results' sections of the same and have not found any evidence of selective reporting (Gibson 2003; Valerius 1991). Trial protocols and online data supplements were available for three trials; all outcomes stated in these were reported in the full papers (EARLY 2019; OPTIMIZE 2018; TORPEDO 2020). One trial has only published results online, but all outcomes stated on the registry appear in the report (ALPINE2 2017).

Other potential sources of bias

We judged one trial to have a high potential risk of bias from other sources (Gibson 2003). Investigators planned to recruit 98 participants, but the trial was stopped early by the Data Monitoring Committee after interim analysis of the first 21 participants showed a statistically significant microbiological effect in favour of the tobramycin‐treated group (Gibson 2003). This trial was supported in part by Chiron, the manufacturer of the inhaled tobramycin (Gibson 2003).

We judged three trials to have an unclear risk of bias (ALPINE2 2017; Proesmans 2013; Ratjen 2010). ALPINE2 2017 was only published as a trial registration document and there was insufficient information for us to adequately assess other potential risks of bias. Proesmans 2013 measured the primary outcome at different time points in different treatment groups: at 28 days in the inhaled tobramycin group and three months in the colistin with ciprofloxacin group. The third trial recruited fewer participants than planned; the total number of planned randomised participants was 100, but 35 from the recruited cohort of 123 were not randomised: 31 because of high P aeruginosa antibody levels (which led the investigators to believe that they were chronically infected with P aeruginosa); one for an adverse event; one where consent was withdrawn; one for a protocol deviation; and one 'other' (unspecified) reason (Ratjen 2010). Therefore, the trial investigators actually randomised 88 participants and the primary outcome was evaluable in 65 of these (Ratjen 2010). The trial results cannot be generalised to a population where anti‐Pseudomonas antibodies are not measured. Furthermore, like the earlier Gibson 2003 trial, this trial was initially supported by Chiron and later Novartis Pharma, the manufacturer of TSI (Ratjen 2010).

We did not identify any potential risks of bias from other sources in seven trials published with full papers and judged these to have a low risk of bias (EARLY 2019; OPTIMIZE 2018; Taccetti 2012; TORPEDO 2020; Treggiari 2011; Valerius 1991; Wiesemann 1998).

One issue which may have unknowingly introduced bias is the fact that individual trial participants can present very differently at baseline with the same diagnosis. For example, one person may present with a positive P aeruginosa culture yet have few symptoms, whilst another may have the symptoms of an exacerbation. Most of the included studies only included "stable" participants and excluded those who had signs and symptoms of an exacerbation (ALPINE2 2017; Gibson 2003; OPTIMIZE 2018; Proesmans 2013; Ratjen 2010), but it is unclear whether definitions were comparable between trials and whether this baseline difference may lead to a difference in the effectiveness of treatments.

Effects of interventions

We graded the certainty of evidence for those outcomes included in the summary of findings tables. For the descriptions of these gradings please refer to summary of findings Table 1 to summary of findings Table 10.

Please note: in the sections below, the review authors have only presented the outcomes and time points for which they have data or narrative information in order to minimise the length of this text section. Missing outcomes indicate that investigators did not include them or report on them in their trials.

Tobramycin solution for inhalation (TNS) versus placebo

This comparison included three trials with 94 participants (EARLY 2019; Gibson 2003; Wiesemann 1998). The certainty of evidence for this comparison is presented in summary of findings Table 1.

Primary outcome

1. Eradication of P aeruginosa from the respiratory tract

a. Clearance of P aeruginosa from BAL, sputum or oropharyngeal cultures

The Wiesemann 1998 trial gave a very different dose of TNS (80 mg twice daily) compared to the Gibson 2003 and EARLY 2019 trials (300 mg twice daily). In the EARLY 2019 trial and the Gibson 2003 trial, fewer children in the TNS group had a positive culture after 28 days compared to placebo (OR 0.04, 95% CI 0.01 to 0.15). In the Gibson 2003 trial, fewer children who received TNS had a positive BAL at one month (OR 0.01, 95% CI 0.00 to 0.30), but not at two months (OR 0.21, 95% CI 0.03 to 1.47; Analysis 1.1). Results were not available for all the participants in the Wiesemann 1998 trial, thereby precluding an intention‐to‐treat analysis. Wiesemann 1998 was able to demonstrate a reduction in the odds of a positive culture from the respiratory tract specimen at two months (OR 0.10, 95% CI 0.01 to 0.90); six months (OR 0.06, 95% CI 0.00 to 0.92); and 12 months of treatment (OR 0.02, 95% CI 0.00 to 0.67), but not at one or three months (very low‐certainty evidence; Analysis 1.2).

An available‐case analysis of the data presented in the Wiesemann 1998 trial showed that, when combined with the data from the Gibson 2003 and EARLY 2019 trials, there was a reduction in the odds of a positive culture in the treatment group compared to the placebo group both at one month (OR 0.06, 95% CI 0.02 to 0.18; low‐certainty evidence), and with just the Gibson 2003 and Wiesemann 1998 trials at two months (OR 0.15, 95% CI 0.03 to 0.65; Analysis 1.3).

A sensitivity analysis following imputation of the missing data to provide best‐case and worst case‐scenarios for the combined analysis showed a range of possible results. The best‐case scenario showed a reduction in the odds of a positive culture of P aeruginosa in the treatment group at both one month (OR 0.06, 95% CI 0.02 to 0.17) and two months (OR 0.14, 95% CI 0.03 to 0.60; Analysis 1.4). Furthermore, these imputed data also showed a difference in favour of TNS at six months (OR 0.04, 95% CI 0.00 to 0.48) and 12 months (OR 0.01, 95% CI 0.00 to 0.26), but not at three months (Analysis 1.4). In the worst‐case scenario the odds of a positive culture was reduced at one month (OR 0.07, 95% CI 0.02 to 0.19) and two months (OR 0.18, 95% CI 0.04 to 0.73), but not at three, six or 12 months when only Wiesemann 1998 reported data (Analysis 1.5).

Secondary Outcomes

1. Mortality

Mortality was not included as an outcome in any of the three trials, but there were no reported deaths during any of the trial periods (EARLY 2019; Gibson 2003; Wiesemann 1998).

3. Spirometric lung function

Wiesemann 1998 reported no change in spirometric pulmonary function during or after the treatment period, but no data were given. Neither remaining trial assessed nor reported on spirometric lung function; most of the participants were too young to perform spirometry reliably (EARLY 2019; Gibson 2003). The certainty of evidence is very low.

4. Growth and nutritional status

Only the trial by Gibson 2003 presented data on weight (kg). There was no evidence of any difference found between the two groups in the change in weight from baseline (trial entry) and subsequent weights measured at one month and two months (Analysis 1.6).

6. Isolation of other micro‐organisms

Gibson 2003 reported no changes in the prevalence of other micro‐organisms, including multiresistant organisms, cultured from respiratory secretions. Neither of the remaining trials collected data on this outcome (EARLY 2019; Wiesemann 1998).

7. Adverse effects of antibiotics

Two trials reported cough in association with inhalation, but there was no evidence of any difference between groups (OR 0.76, 95% CI 0.10 to 5.77; very low‐certainty evidence; Analysis 1.7). There was no evidence of a difference in serum creatinine levels or auditory threshold between the groups; however, the number of participants were small (Gibson 2003). Wiesemann 1998 reported one withdrawal from the placebo group because of cough but did not report on the presence or absence of cough in other participants.

Additional outcomes which have arisen during the review

2. Clinical and radiological scores

Only the Gibson 2003 trial reported modified ShwachmanTreggiari 2011 scores, which were recorded at one month and two months from enrolment and were expressed as both mean scores with SDs and mean change from baseline with SDs. There was no evidence of any differences between the two groups in changes in either mean scores or modified Schwachman scores from baseline at either one month or two months (Analysis 1.8).

Inhaled tobramycin (28 days) versus inhaled tobramycin (56 days)

This intervention comparing 28 days TNS with 56 days TNS included one trial of 123 participants, of whom 88 were randomised (Ratjen 2010). The certainty of evidence for this comparison is presented in summary of findings Table 2.

Primary outcome

1. Eradication of P aeruginosa from the respiratory tract

a. Clearance of P aeruginosa from BAL, sputum or oropharyngeal cultures

This outcome was not evaluated; data were presented in the paper at one month, when participants were all given the initial 28 days of TNS before randomisation and were excluded if they had raised P aeruginosa antibody levels (Ratjen 2010).

b. Time to next isolation of P aeruginosa from BAL, sputum or oropharyngeal cultures

The median time to recurrence was 26.12 months in the 28‐day treatment group and 25.82 months in the 56‐day treatment group. There was no evidence of any differences between groups (HR 0.81, 95% CI 0.37 to 1.76; Analysis 2.1). We deemed the certainty of evidence for this outcome to be low.

Secondary Outcomes

1. Mortality

There were no deaths reported (Ratjen 2010).

3. Spirometric lung function

The paper presented data in a table for the median change from baseline to three months and to 27 months for FEV₁ % predicted, FVC % predicted and FEF_25-75 % predicted; however, reported data were combined for both the 28‐day and the 56‐day treatment groups. The paper states that there were "no major short‐ or long‐term changes in spirometric parameters observed during the study period" (Ratjen 2010). We assessed the certainty of this evidence to be very low.

4. Growth and nutritional status

The authors did not report any differences in weight, height or BMI and only presented a summary statement indicating that "no significant difference" was found in weight, height or BMI. The trial authors did not provide any data (Ratjen 2010). The certainty of this evidence is very low.

5. Frequency of respiratory exacerbations

Two participants allocated to the 56‐day treatment group were hospitalised on one occasion, each for a pulmonary exacerbation. One of these isolated P aeruginosa and was treated with IV ceftazidime and tobramycin. When entered into the analysis this showed no evidence of any difference between groups (very low‐certainty evidence; Analysis 2.2).

6. Isolation of other micro‐organisms

There were no consistent trends reported in the isolation of non‐P aeruginosa organisms (one isolate only of Stenotrophomonas maltophilia, which was seen in the 28‐day arm) (very low‐certainty evidence).

7. Adverse effects of antibiotics

Adverse events up to three months that were considered possibly or probably related to treatment were reported by 14 participants in each treatment group, with the majority being related to dysphonia in both treatment groups (11% and 14%, respectively) and cough in the 28‐day group (9%). There was no evidence of any differences between treatment groups for any of the reported adverse events at any time point; however, we note that, given the number of different events measured and the increased probability of type I statistical error and spurious group differences, numerical results of these two analyses must be carefully interpreted (Analysis 2.3; Analysis 2.4). The certainty of this evidence is very low.

Additional outcomes which have arisen during the review

No additional outcomes were reported for this comparison.

Cycled inhaled tobramycin versus culture‐based inhaled tobramycin

This comparison of cycled TNS (with oral ciprofloxacin or placebo) with culture‐based TNS (with oral ciprofloxacin or placebo) included one trial, with 306 participants randomised and data analysed from 304 participants who received treatment (Treggiari 2011). The certainty of evidence for this comparison is presented in summary of findings Table 3.

Primary outcome

1. Eradication of P aeruginosa from the respiratory tract

a. Clearance of P aeruginosa from BAL, sputum or oropharyngeal cultures

Treggiari 2011 reported that 43 out of 148 children on cycled therapy had one or more isolates of P aeruginosa compared to 67 out of 150 children on culture‐based therapy, giving an effect in favour of cycled therapy (OR 0.51, 95% CI 0.31 to 0.82; Analysis 3.1). We deemed the certainty of this evidence to be moderate. The main trial publication reports an age‐adjusted OR, using generalised estimating equations, with robust variance, specifying a logit link and assuming an independence working correlation (Treggiari 2011). This may explain the difference between the trial publication and the findings of this review.

Secondary Outcomes

1. Mortality

No deaths were reported in either arm (Treggiari 2011).

3. Spirometric lung function

The included trial reports the mean 70‐week change in FEV₁ % predicted, but there was no evidence of any difference between the two arms (Analysis 3.2) (low‐certainty evidence).

4. Growth and nutritional status

The Treggiari 2011 trial reports the mean 70‐week change from baseline in weight (kg) for each treatment arm, but there was no evidence of any difference between arms (Analysis 3.3). The trial also reports data for the change from baseline in height (cm) for each arm at the same time point; again the MD did not show any evidence of a difference between groups (Analysis 3.4). We deemed this to be moderate‐certainty evidence.

5. Frequency of respiratory exacerbations

A primary outcome in the Treggiari 2011 trial was the time to a severe pulmonary exacerbation (i.e. an exacerbation requiring IV antibiotics or hospitalisation or both). The analysis shows no evidence of any difference in time to a severe exacerbation (Analysis 3.5).

Data on the frequency of severe exacerbations during the 70‐week follow‐up period were also presented in the paper. From our analysis, the data indicate no evidence of any difference between groups (Analysis 3.6).

Treggiari 2011 also reported a secondary outcome of time to pulmonary exacerbation of any severity (including any exacerbation treated with IV, inhaled or oral antibiotics or requiring hospitalisation). The results of our analysis are slightly different to those reported in the paper, but still show no difference in time to any exacerbation (Analysis 3.7).

Finally, the number of exacerbations of any severity was also reported. In our analysis, the OR was not different between cycled and culture‐based therapy (moderate‐certainty evidence; Analysis 3.8).

6. Isolation of other micro‐organisms

The Treggiari 2011 trial reported the number of participants in each arm with one or more isolates of the emerging pathogen S maltophilia. There was probably no difference between cycled and culture‐based therapy (moderate‐certainty evidence; Analysis 3.9).

7. Adverse effects of antibiotics

Regarding the incidence of serious adverse effects, Treggiari 2011 did not report any difference between treatment arms, although adverse events attributable to antibiotic therapy were not recorded separately from adverse events which were unlikely to be related to the study intervention. Our results agree with those reported in the paper (moderate‐certainty evidence; Analysis 3.10).

Additional outcomes which have arisen during the review

No additional outcomes were reported for this comparison.

Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin therapy

As discussed under Description of studies, the Treggiari 2011 trial randomised participants to cycled versus culture‐based TNS therapy and then to oral ciprofloxacin versus placebo for two weeks with each 28‐day course of TNS. This section presents the comparison of outcomes in the ciprofloxacin and placebo arms. The certainty of evidence for this comparison is presented in summary of findings Table 4.

Primary outcome

1. Eradication of P aeruginosa from the respiratory tract

a. Clearance of P aeruginosa from BAL, sputum or oropharyngeal cultures

Treggiari 2011 reported that 49 out of 146 children on oral ciprofloxacin had one or more isolates of P aeruginosa compared to 55 out of 152 children on placebo. The data for this outcome show there is probably no difference between treatment groups (OR 0.89, 95% CI 0.55 to 1.44; 1 trial, 298 participants; moderate‐certainty evidence; Analysis 4.1). Age group–adjusted ORs are reported in the trial paper; in our analysis, we did not adjust for age.

Secondary Outcomes

1. Mortality

No deaths were reported in either arm (Treggiari 2011).

3. Spirometric lung function

The included trial reports the mean 70‐week change in FEV₁ % predicted, but there was no evidence of any difference between the two arms (low‐certainty evidence; Analysis 4.2).

4. Growth and nutritional status

The Treggiari 2011 trial reports the mean 70‐week change from baseline in weight (kg) for each treatment arm; there was no evidence of any difference between arms (Analysis 4.3). The trial also reports data for the change from baseline in height (cm) for each arm; again there was probably no difference between arms (Analysis 4.4) (moderate‐certainty evidence).

5. Frequency of respiratory exacerbations

A primary outcome in the Treggiari 2011 trial was the time to a severe pulmonary exacerbation (i.e. an exacerbation requiring IV antibiotics or hospitalisation, or both). Again, for the ciprofloxacin versus placebo comparison, there was no evidence of any difference in time to a severe exacerbation (Analysis 4.5).

Data on the frequency of severe exacerbations during the 70‐week follow‐up period are also presented in the paper. From our analysis, the OR is not different between groups (moderate‐certainty evidence; Analysis 4.6).

We analysed the outcome 'time to pulmonary exacerbation (any severity)', including any exacerbation treated with IV, inhaled or oral antibiotics or requiring hospitalisation (Analysis 4.7). There was no evidence of any difference between ciprofloxacin and placebo in time to exacerbation (any severity).

Finally, the number of exacerbations of any severity was not different between ciprofloxacin and placebo (Analysis 4.8).

6. Isolation of other micro‐organisms

In the Treggiari 2011 trial, there was no evidence of any difference between ciprofloxacin and placebo in the number of isolates of S maltophilia (moderate‐certainty evidence; Analysis 4.9).

7. Adverse effects of antibiotics

Treggiari 2011 did not report any difference between treatment arms in the incidence of adverse events, although adverse events attributable to antibiotic therapy were not recorded separately from adverse events which were unlikely to be related to the trial intervention. Our analysis showed there is probably no difference between arms in the number of participants with one or more serious adverse events (moderate‐certainty evidence; Analysis 4.10).

Additional outcomes which have arisen during the review

None of the additional outcomes were reported for this comparison.

Oral ciprofloxacin plus inhaled colistin versus inhaled tobramycin

This comparison of oral ciprofloxacin plus inhaled colistin (three months) with TNS (28 days) included only one trial with 58 participants (29 in each treatment group) (Proesmans 2013). The certainty of evidence for this comparison is presented in summary of findings Table 5.

Primary outcome

1. Eradication of P aeruginosa from the respiratory tract

a. Clearance of P aeruginosa from BAL, sputum or oropharyngeal cultures

At some point in the six months following treatment, P aeruginosa was isolated in 10 out of 29 participants enrolled to the inhaled colistin with oral ciprofloxacin arm compared to 16 out of 29 in the TNS arm (OR 0.43, 95% CI 0.15 to 1.23; Analysis 5.1) and at 24 months (OR 0.76, 95% CI 0.24 to 2.42; Analysis 5.1). There was no evidence of a difference between groups (very low‐certainty evidence).

Secondary Outcomes

1. Mortality

There were no deaths in either arm (Proesmans 2013).

3. Spirometric lung function

The median change from baseline in FEV₁ (% predicted) for all the participants was ‐1%. The changes were not reported separately for each treatment arm (Proesmans 2013). We assessed the certainty of this evidence as very low.

4. Growth and nutritional status

Both BMI z score and weight z score were reported not to have changed "significantly" for trial participants as a whole, but numerical data were not reported (very low‐certainty evidence) (Proesmans 2013).

5. Frequency of respiratory exacerbations

The trial authors reported that, during the first six months of follow‐up, there was no difference between the two treatment arms in number of oral antibiotic treatment days. These oral antibiotics were given for symptoms and not because of failed eradication. However, numerical data were not reported (Proesmans 2013).

7. Adverse effects of antibiotics

One participant was reported to have developed a severe cough with TNS, and there were no events in the ciprofloxin and colistin group (Analysis 5.2). No other adverse effects were reported, and we deemed the certainty of evidence to be very low.

Additional outcomes which have arisen during the review

None of our additional outcomes were reported for this comparison.

Oral ciprofloxacin plus inhaled colistin versus oral ciprofloxacin plus inhaled tobramycin

This comparison of oral ciprofloxacin plus inhaled colistin with oral ciprofloxacin plus TNS included one trial with 223 participants (Taccetti 2012). The certainty of evidence for this comparison is presented in summary of findings Table 6.

Primary outcome

1. Eradication of P aeruginosa from the respiratory tract

a. Clearance of P aeruginosa from BAL, sputum or oropharyngeal cultures

In the inhaled colistin plus oral ciprofloxacin group, P aeruginosa was isolated within the first six months from 39 out of 105 participants (37.1%) and in the TNS plus oral ciprofloxacin group from 41 out of 118 participants (34.7%) (Taccetti 2012). When data were analysed, the rate of isolation of P aeruginosa between the two arms was not different (OR 1.11, 95% CI 0.64 to 1.92; Analysis 6.1). At a median follow‐up period of 16 months, P aeruginosa had been isolated from 36 out of 97 participants in the colistin with ciprofloxacin arm for whom data were available and from 24 out of 108 participants in the TNS with ciprofloxacin arm; the two arms did not differ (OR 1.28, 95% CI 0.72 to 2.29; low‐certainty evidence; Analysis 6.1). The trial authors reported that subgroup analyses by gender, age (one to five years; five to 12 years and over 12 years), lung function (FEV₁ % predicted less than or greater than 70%) and participants with first ever isolation of P aeruginosa failed to show any differences between groups (Taccetti 2012).

Secondary Outcomes

1. Mortality

No deaths were reported (Taccetti 2012).

3. Spirometric lung function

Following treatment, after a mean (SD) time of observation of 54 (39) days, the mean (SD) relative change in FEV₁ % predicted from baseline did not differ between groups with 2.15 (8.50)% in the inhaled colistin plus oral ciprofloxacin group compared to 4.55 (11.54)% in the TNS plus oral ciprofloxacin group (Analysis 6.2).

6. Isolation of other micro‐organisms

There was an observation that S maltophilia was isolated more frequently in the follow‐up period than before eradication treatment, but our analysis found no evidence of any difference between the two groups during follow‐up for isolation of: S maltophilia,Achromobacter xylosoxidans or Aspergillus species (moderate‐certainty evidence; Analysis 6.3).

7. Adverse effects of antibiotics

There were a total of 38 out of 223 randomised participants (17%) who discontinued treatment early; of these, 17 were from the inhaled colistin plus oral ciprofloxacin group and 21 from the TNS plus oral ciprofloxacin group (Analysis 6.4). There were a number of reasons for these discontinuations, including vomiting, photosensitivity, wheeze and pulmonary exacerbation. The certainty of evidence is moderate.

Additional outcomes which have arisen during the review

None of the additional outcomes were reported for this comparison.

Inhaled tobramycin plus oral azithromycin compared to inhaled tobramycin plus oral placebo

We included one trial (221 participants) comparing TNS plus azithromycin to TNS plus oral placebo (OPTIMIZE 2018). The certainty of evidence for this comparison is presented in summary of findings Table 7.

Primary outcome

1. Eradication of P aeruginosa from the respiratory tract

a. Clearance of P aeruginosa from BAL, sputum or oropharyngeal cultures

Of those participants who were positive for P aeruginosa at baseline and had a culture result available at the end of the first treatment quarter, there was no evidence of any difference in eradication rates between groups (OPTIMIZE 2018). In the azithromycin group, 35 out of 52 (67.3%) participants converted to a negative culture whilst 26 of 39 (66.7%) participants in the placebo group converted to a negative culture (RR 1.01, 95% CI 0.75 to 1.35; low‐certainty evidence; Analysis 7.1).

b. Time to next isolation of P aeruginosa from BAL, sputum or oropharyngeal cultures

We found no evidence of any differences between treatment groups in time to recurrence after the first treatment quarter, with 41 out of 103 participants in the azithromycin group and 38 out of 97 participants in the placebo group experiencing a recurrence in the follow‐up period (HR 1.00, 95% CI 0.64 to 1.55; P = 0.99). The authors reported that when the results were adjusted for baseline P aeruginosa status, the overall odds of recurrence in the azithromycin group were slightly higher than the placebo group although not "significant" (OR 1.33, 95% CI 0.80 to 2.23; P = 0.27) (OPTIMIZE 2018).

Secondary Outcomes

1. Mortality

No deaths were reported in either treatment group (OPTIMIZE 2018).

3. Spirometric lung function

Data reported in the paper showed no evidence of any difference between groups in mean change in FEV₁ % predicted over the 18‐month period (MD ‐1.71%, 95% CI ‐7.76 to 4.34; P = 0.384; low‐certainty evidence). The authors also reported that there was no difference between groups in any of the other spirometry parameters, but the data were not presented (OPTIMIZE 2018).

4. Growth and nutritional status

There was an improvement in weight (kg) in the azithromycin group compared to the placebo group (MD 1.27 kg, 95% CI 0.01 to ‐2.52; P = 0.046; moderate‐certainty evidence), but no evidence of any difference between groups in height (MD 0.97 cm, 95% CI ‐0.73 to 2.68; P = 0.36; moderate‐certainty evidence) (OPTIMIZE 2018).

5. Frequency of respiratory exacerbations

Time to next exacerbation was decreased in the azithromycin group compared to the placebo group (HR 0.56, 95% CI 0.37 to 0.83; P = 0.004). There was a 44% decreased risk of exacerbation associated with azithromycin. The number of participants experiencing an exacerbation by the end of the study was lower in the azithromycin group compared to the placebo group (RR 0.75, 95% CI 0.56 to 1.00; moderate‐certainty evidence; Analysis 7.2).

Need for additional antibiotics

There was no evidence of any difference between groups in the need for additional IV antibiotics (RR 1.01, 95% CI 0.60 to 1.69; Analysis 7.3), inhaled antibiotics (RR 1.35, 95% CI 0.31 to 5.87; Analysis 7.3) or oral antibiotics (RR 0.89, 95% CI 0.74 to 1.08; Analysis 7.3) (OPTIMIZE 2018).

Hospitalisations

We found no evidence of any difference between groups in the number of participants requiring hospitalisation during the trial (RR 0.97, 95% CI 0.59 to 1.59; Analysis 7.4) (OPTIMIZE 2018).

6. Isolation of other micro‐organisms

The emergence of other pathogens during the study was found to be comparable between groups, and numbers were small. We found moderate‐certainty evidence for the pathogens reported, which included methicillin‐resistant Staphylococcus aureus (MRSA) (RR 0.83, 95% CI 0.35 to 1.94; Analysis 7.5), Burkholderia cepacia (RR 0.32, 95% CI 0.01 to 7.71; Analysis 7.5), A xylosoxidans (RR 1.59, 95% CI 0.39 to 6.47; Analysis 7.5), S maltophilia (RR 1.65, 95% CI 0.72 to 3.76; Analysis 7.5), Haemophilus influenzae (RR 1.13, 95% CI 0.58 to 2.21; Analysis 7.5) and NTM (RR 0.67, 95% CI 0.05 to 9.66; Analysis 7.5) (OPTIMIZE 2018).

7. Adverse effects of antibiotics

There was no evidence of differences in the occurrence of serious adverse events between the treatment groups (moderate‐certainty evidence). The number of participants experiencing any adverse event is shown in Analysis 7.6. We found no evidence of differences for gastro‐intestinal disorders, general disorders and administration site conditions, metabolism and nutrition disorders, infections and infestations, nervous system disorders, renal and urinary disorders or respiratory, thoracic and mediastinal disorders (OPTIMIZE 2018). The investigators also stated that no participants experienced temporary or permanent sensorineural hearing loss in either group and there were no differences between groups in abnormal electrocardiograms (OPTIMIZE 2018).

Oral ciprofloxacin and inhaled colistin versus no treatment

This comparison included only one trial with 26 participants (Valerius 1991). The certainty of evidence for this comparison is presented in summary of findings Table 8.

Primary outcome

None of our primary outcomes were reported.

Secondary Outcomes

7. Adverse effects of antibiotics

Valerius 1991 did not describe cough specifically, but reported that there were no adverse effects in either group. Certainty of evidence was very low.

Additional outcomes which have arisen during the review

1. Time to chronic infection

We defined this as the presence of P aeruginosa in each monthly sputum sample for six consecutive months or the presence of precipitating antibodies to P aeruginosa, or both. From the data provided for the Valerius 1991 trial, it was possible to calculate the proportion of participants in each group who were defined as chronically infected with P aeruginosa from respiratory secretions at three, six, 12 and 24 months. The odds of being chronically infected with P aeruginosa were reduced in the treatment group compared to the placebo group after 24 months (OR 0.12, 95% CI 0.02 to 0.79; Analysis 8.1). We found no evidence of a difference between the two groups at the other time points. No other trials in the review used this outcome measure to express their findings.

Inhaled AZLI for 14 days plus placebo for 14 days compared to inhaled AZLI for 28 days

Only one trial with 149 participants compared 14 days of AZLI followed by 14 days of placebo to 28 days of AZLI (ALPINE2 2017). To date, the results of the trial are only available via the online trials registry; the certainty of evidence for this comparison is presented in summary of findings Table 9.

1. Eradication of P aeruginosa from the respiratory tract

a. Clearance of P aeruginosa from BAL, sputum or oropharyngeal cultures

In the 28‐day period after treatment, 55.9% of participants in the intervention group (AZLI 14 days) had negative P aeruginosa cultures compared to 63.4% in the control group (MD ‐7.50%, 95% CI ‐24.80 to 9.80; 1 trial, 139 participants; very low‐certainty evidence; Analysis 9.1). The CIs are wide, suggesting there may be little real difference between groups (ALPINE2 2017).

b. Time to next isolation of P aeruginosa from BAL, sputum or oropharyngeal cultures

The trial also reported the time to recurrence of P aeruginosa over a follow‐up period of 108 weeks and stated that in the intervention group the median time to recurrence was 19.3 months. The median value for the control group was not available as the calculated percentiles of event rate were not reached (ALPINE2 2017).

Secondary Outcomes

1. Mortality

No deaths were reported in either group during the follow‐up period of the trial (ALPINE2 2017).

7. Adverse effects of antibiotics

The trial did not specifically report adverse effects of antibiotics, but did report on the number of participants in each group who experienced serious adverse events (ALPINE2 2017). Five out of 74 (6.76%) participants in the AZLI 14‐day group experienced adverse events compared to four out of 75 (5.33%) in the AZLI 28‐day group (RR 1.27, 95% CI 0.35 to 4.53; Analysis 9.2).

Additional outcomes which have arisen during the review

No additional outcomes were reported for this comparison.

IV ceftazidime and tobramycin compared with oral ciprofloxacin (both treatment regimens in conjunction with three months nebulised colistin)

One trial, which included 286 adults and children, is included in this comparison (TORPEDO 2020). The certainty of evidence for this comparison is presented in summary of findings Table 10.

Primary outcome

a. Clearance of P aeruginosa from BAL, sputum or oropharyngeal cultures

In the IV group, 55 out of 125 participants had eradicated P aeruginosa at three months compared to 68 of 130 participants in the oral group. This showed no difference in the chance of achieving eradication at three months and maintaining it to 15 months between the group receiving IV compared to the oral antibiotic group when given inhaled colistin alongside (RR 0.84, 95% CI 0.65 to 1.09; P = 0.18; Analysis 10.1; high‐certainty evidence).

b. Time to next isolation of P aeruginosa from BAL, sputum or oropharyngeal cultures

The trial investigators reported data showing no evidence of any difference in the time to the next recurrence of P aeruginosa between the intravenous and the oral group (HR 1.31, 95% CI 0.93 to 1.85; P = 0.12) (TORPEDO 2020).

Secondary Outcomes

1. Mortality

There were no deaths in either group throughout the trial (TORPEDO 2020).

2. Quality of life

A total of 134 out of 285 participants completed CFQ‐R quality of life questionnaires (only for children aged six and over). We found no evidence of any differences between treatment groups across any of the domains in the questionnaire. The trial also reported no difference between groups with regard to the median number of days of absenteeism (P = 0.62 for carer responses and P = 0.26 for participant completed responses) (TORPEDO 2020).

3. Spirometric lung function

There was no difference between IV treatment and oral treatment with respect to FEV₁ % predicted (MD 2.08%, 95% CI ‐0.81 to 4.97; Analysis 10.2) or FEF_25-75 % predicted (MD 3.46%, 95% CI ‐3.35 to 10.27; Analysis 10.4). At the end of the trial, FVC % predicted was higher in the IV treatment group (MD 3.14%, 95% CI 0.31 to 5.97; high‐certainty evidence; Analysis 10.3) (TORPEDO 2020).

4. Growth and nutritional status

Our analysis showed no difference between groups for any of the growth and nutritional status indicators: height‐for‐age z score (MD ‐0.03, 95% CI ‐0.13 to 0.07; high‐certainty evidence; Analysis 10.5); weight‐for‐age z score (MD ‐0.02, 95% CI ‐0.15 to 0.11; high‐certainty evidence; Analysis 10.6); and BMI z score (paediatric) (MD 0.01, 95% CI ‐0.12 to 0.14; high‐certainty evidence; Analysis 10.7). There were a lot fewer adults recruited into the trial (n = 15), and for those participants a different scoring method, BMI (kg/m²), was used to reflect growth and nutritional status. This outcome measure also showed no evidence of any difference between treatment groups, BMI (kg/m²) in adults (MD ‐0.74, 95% CI ‐3.40 to 1.92; high‐certainty evidence; Analysis 10.8) (TORPEDO 2020).

5. Frequency of respiratory exacerbations

Number of participants experiencing an exacerbation by the end of the study

Over the course of the study 38 out of 137 participants in the IV group experienced an exacerbation compared with 52 out of 156 in the oral antibiotic group; however, when analysed there was no difference seen between the groups (RR 0.78, 95% CI 0.55 to 1.10; high‐certainty evidence; Analysis 10.9).

Hospitalisations

In the period after initial eradication, fewer participants were admitted to hospital in the IV group compared to the oral group (RR 0.69, 95% CI 0.50 to 0.95; Analysis 10.10). The trial also reported on the median number of days in hospital during the three‐month treatment phase (median in both groups was zero days (range 0 to 29 days for the IV group (n = 135) and (range 0 to 15 days for the oral group (n = 143)) (P = 0·066). In the 12‐month post‐treatment phase, the median number of days in hospital was also zero for both groups (range 0 to 69 days for IV treatment group (n = 129) and 0 to 64 days for the oral treatment group (n = 136); P = 0·005) (TORPEDO 2020).

6. Isolation of other micro‐organisms

There was no difference between the oral and IV groups in the isolation of other pathogens, including MRSA (MD 2.07, 95% CI 0.39 to 11.14; high‐certainty evidence; Analysis 10.11); B cepacia (MD 0.51, 95% CI 0.10 to 2.76; high‐certainty evidence; Analysis 10.11); Candida spp (MD 1.04, 95% CI 0.78 to 1.40; high‐certainty evidence; Analysis 10.11); and Aspergillus spp (MD 0.72, 95% CI 0.38 to 1.37; high‐certainty evidence; Analysis 10.11) (TORPEDO 2020).

7. Adverse effects of antibiotics

There was probably no difference in serious adverse effects (RR 0.97, 95% CI 0.43 to 2.16; moderate‐certainty evidence; Analysis 10.12) or non‐serious adverse effects (RR 0.97, 95% CI 0.75 to 1.24; moderate‐certainty evidence; Analysis 10.12) between groups, except for upper respiratory tract infections (URTIs) where there were fewer incidences in the oral antibiotic treatment group (RR 6.37, 95% CI 1.44 to 28.21; moderate‐certainty evidence; Analysis 10.12). No serious adverse reactions to antibiotics were reported in either group (TORPEDO 2020).

Additional outcomes

3. Cost‐effectiveness

Overall, oral treatment was less costly than IV treatment (including intervention costs). The incremental difference in mean costs was GBP 5939 lower (95% CI –7107 to –4666) after adjusting for baseline covariates (TORPEDO 2020).

Discussion

Summary of main results

Our review includes 11 trials (with data from 1449 participants) of antibiotic strategies for eradicating P aeruginosa infection in people with CF, conducted over a period of over 30 years. Each trial used a different intervention; up to three trials could be combined in meta‐analyses for some outcomes, but the majority of comparisons had only one or two studies per outcome. In one trial, an early interim‐analysis was performed due to slow accrual (Gibson 2003).

Inhaled tobramycin versus placebo

This comparison included three trials with 94 participants (EARLY 2019; Gibson 2003; Wiesemann 1998). The trials administered two different doses of TNS; Wiesemann 1998 used 80 mg twice daily compared to the Gibson 2003 trial and the EARLY 2019 trial, which both used 300 mg twice daily.

There may be a slight improvement in eradication with TNS (low‐certainty evidence). The trials with the higher dose reported that fewer participants were still positive for P aeruginosa in respiratory secretions in the participants receiving antibiotics than from those receiving placebo at one month and two months; combined data also showed antibiotic treatment may lead to fewer positive respiratory culture for P aeruginosa at one month (OR 0.06, 95% CI 0.02 to 0.18; 3 trials, 89 participants; low‐certainty evidence; Analysis 1.3) and two months (OR 0.15, 95% CI 0.03 to 0.65; 2 trials, 38 participants; Analysis 1.3) after the start of treatment (Gibson 2003; Wiesemann 1998). We are uncertain whether there is a reduction in the odds of a positive culture at 12 months (OR 0.02, 95% CI 0.00 to 0.67; 1 trial, 12 participants; Analysis 1.2).

We are uncertain whether there is any difference in spirometric lung function, growth and nutrition or isolation of other micro‐organisms between those on TNS and those on placebo. We are also uncertain whether there is any difference between groups in adverse effects.

Inhaled tobramycin (28 days) versus inhaled tobramycin (56 days)

The Ratjen 2010 trial (n = 88) ran from November 2003 until January 2008 and compared 28‐day and 56‐day treatment with TNS; there was no difference in time to next isolation between treatments (HR 0.81, 95% CI 0.37 to 1.76; low‐certainty evidence; Analysis 2.1).

We are uncertain whether there was any difference between treatments in terms of spirometric lung function, growth and nutrition, frequency of exacerbations or isolation of other micro‐organisms. Similarly, there were no differences in adverse effects between groups (Ratjen 2010).

Cycled inhaled tobramycin versus culture‐based inhaled tobramycin

The Treggiari 2011 trial was the largest trial of P aeruginosa eradication in CF reported so far, randomising and reporting data on 304 children (aged one to 12 years). The trial used a complex, four‐arm design, comparing cycled with culture‐based treatment with TNS and also additional oral ciprofloxacin versus placebo. The trial was adequately powered for its two primary outcome measures (time to severe pulmonary exacerbation and proportion of P aeruginosa positive cultures). Our analysis found cycled therapy may lead to fewer isolates of P aeruginosa from the respiratory tract (OR 0.51, 95% CI 0.31 to 0.82; moderate‐certainty evidence; Analysis 3.1), although the trial publication reported age‐adjusted OR and found no difference between groups.

Cycled therapy may make no difference to FEV₁ % predicted (low‐certainty evidence) and probably makes no difference to growth and nutrition outcomes, weight and height (moderate‐certainty evidence). There is probably no difference in the frequency of pulmonary exacerbations (OR 0.75, 95% 0.48 to 1.17; moderate‐certainty evidence; Analysis 3.8). Similarly, there is probably no difference in isolation of other micro‐organisms (S maltophilia) (OR 1.18, 95% CI 0.65 to 2.12; moderate‐certainty evidence; Analysis 3.9). There is probably no difference between cycled and culture‐based therapy in adverse effects (moderate‐certainty evidence; Analysis 3.10).

Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin therapy

The Treggiari 2011 trial (304 children randomised) looked at the effect of adding ciprofloxacin or placebo to cycled and culture‐based therapy and found that there is probably no difference made by adding either ciprofloxacin or placebo in eradicating P aeruginosa (OR 0.89, 95% CI 0.55 to 1.44; 297 participants; moderate‐certainty evidence; Analysis 4.1). Adding ciprofloxacin may make little difference to spirometric lung function (low‐certainty evidence; Analysis 4.2) and probably no difference in terms of growth and nutritional outcomes (moderate‐certainty evidence; Analysis 4.3; Analysis 4.4). There was also probably no difference in terms of the frequency of exacerbations (moderate‐certainty evidence; Analysis 4.8), isolation of other organisms (moderate‐certainty evidence; Analysis 4.9) or adverse effects (moderate‐certainty evidence; Analysis 4.10).

Oral ciprofloxacin and inhaled colistin versus inhaled tobramycin

One trial (58 participants (29 in each treatment group)) compared oral ciprofloxacin with inhaled colistin (three months) with TNS (28 days) (Proesmans 2013).

Our analysis found no difference between groups in terms of eradication of P aeruginosa at up to six months (OR 0.43, 95% CI 0.15 to 1.23; very low‐certainty evidence; Analysis 5.1) or at 24 months (OR 0.76, 95% CI 0.24 to 2.42; very low‐certainty evidence; Analysis 5.1). (Proesmans 2013). The numbers of participants in each group were too low to allow comparisons of superiority between the two eradication regimens to be made. A further possible cause of the low eradication rate in this trial may be that participants were recruited if they had been free of P aeruginosa for at least six months (with negative microbiology samples for at least six months), which is shorter than the 12‐month P aeruginosa‐free interval used by the Leeds definition of 'Pseudomonas‐free' (Lee 2003).

We are uncertain whether there is any difference in spirometric lung function, growth and nutrition or adverse effects (Proesmans 2013).

Inhaled colistin plus oral ciprofloxacin versus inhaled tobramycin plus oral ciprofloxacin

The Taccetti 2012 trial (223 participants) compared TNS with oral ciprofloxacin to inhaled colistin with oral ciprofloxacin, both treatments given over 28 days. At 16 months, there may be no difference in positive respiratory cultures (OR 1.28, 95% CI 0.72 to 2.29; low‐certainty evidence; Analysis 6.1). The included participants had been free of P aeruginosa for at least six months, again at variance with the Leeds definition of Pseudomonas‐free (Lee 2003).

Inhaled tobramycin with oral ciprofloxacin compared to inhaled colistin with oral ciprofloxacin may make no difference to spirometric lung function or isolation of other organisms. There is probably no difference in adverse effects between groups.

Inhaled tobramycin plus oral azithromycin compared to inhaled tobramycin plus oral placebo

One trial (221 participants) compared adding oral azithromycin or placebo to TNS (OPTIMIZE 2018). Investigators found that adding oral azithromycin may make no difference to the number of participants eradicated after three months of treatment (RR 1.01, 95% CI 0.75 to 1.35; low‐certainty evidence; Analysis 7.1). This analysis only included 91 participants who were positive for P aeruginosa at baseline and had a culture result available at the end of the first treatment quarter. The paper reports that there were also no differences in time to recurrence.

At the 18‐month follow‐up, the results reported in the paper showed that adding oral azithromycin may make no difference to FEV₁ % predicted (MD ‐1.71%, 95 % CI ‐7.76 to 4.34; P = 0.384; low‐certainty evidence). The paper reported that there was probably a slight improvement in weight in the oral azithromycin group at the 18‐month follow‐up (MD 1.27 kg, 95 % CI 0.01 to ‐2.52; P = 0.046; moderate‐certainty evidence), although no difference in height (MD 0.97 cm, 95 % CI ‐0.73 to 2.68; P = 0.36; moderate‐certainty evidence) (OPTIMIZE 2018). Adding oral azithromycin probably resulted in fewer participants experiencing an exacerbation by the end of the trial (RR 0.75, 95 % CI 0.56 to 1.00; moderate‐certainty evidence; Analysis 7.2). There was no difference between groups in the occurrence of serious adverse effects (moderate‐certainty evidence; Analysis 7.6).

Oral ciprofloxacin and inhaled colistin versus no treatment

This comparison included only one trial with 26 participants (Valerius 1991). None of our primary outcomes were reported in this comparison but an additional outcome arising during the review (time to chronic infection) was reported. There was no difference in the odds of being chronically infected with P aeruginosa in the treatment group compared to the no treatment group after 12 months (OR 0.17, 95% CI 0.03 to 1.09; Analysis 8.1) (Valerius 1991). No adverse effects were reported in either group.

Inhaled AZLI for 14 days plus placebo for 14 days compared to inhaled AZLI for 28 days

The ALPINE2 2017 trial (149 participants aged between 28 days and 17 years old) compared the effectiveness of 14 days of AZLI followed by 14 days of placebo (74 participants) to 28 days of AZLI (75 participants) in eradicating P aeruginosa. We are uncertain whether 14 days of AZLI improves the eradication of P aeruginosa compared to 28 days as the certainty of evidence has been assessed as very low (very low‐certainty evidence; Analysis 9.1). We are also uncertain whether 14 days of AZLI altered the time to recurrence of P aeruginosa over 108 weeks median time to recurrence for the control group was not available.

There was no difference in adverse reactions to either treatment group (Analysis 9.2). No additional outcomes were reported.

Intravenous ceftazidime with tobramycin compared with oral ciprofloxacin (both treatment regimens in conjunction with three months nebulised colistin)

The TORPEDO 2020 trial (286 participants aged 28 days old and above) compared the use of 14 days of intravenous ceftazidime and tobramycin (n = 137) to a 12‐week course of oral ciprofloxacin (n = 149) for eradicating P aeruginosa; both regimens were combined with 12 weeks of inhaled colistimethate sodium. The investigators found that intravenous ceftazidime made little to no difference to the chance of achieving eradication of P aeruginosa at three months and little to no difference in sustaining eradication at 15 months compared to the oral treatment group (RR 0.84, 95% CI 0.65 to 1.09; P = 0.18; Analysis 10.1; high‐certainty evidence). There was also no difference in time to next isolation of P aeruginosa between both treatment groups (HR 1.31, 95% CI 0.93 to 1.85; P = 0.12).

The paper reported that intravenous therapy made little to no difference in the frequency of respiratory exacerbations (RR 0.78, 95% CI 0.55 to 1.10; high‐certainty evidence; Analysis 10.9) and to the isolation of other pathogens including: MRSA (MD 2.07, 95% CI 0.39 to 11.14; high‐certainty evidence; Analysis 10.11); B cepacia (MD 0.51, 95% CI 0.10 to 2.76; high‐certainty evidence; Analysis 10.11); Candida spp (MD 1.04, 95% CI 0.78 to 1.40; high‐certainty evidence; Analysis 10.11); and Aspergillus spp (MD 0.72, 95% CI 0.38 to 1.37; high‐certainty evidence; Analysis 10.11) compared to the oral group.

During follow up the investigators reported that by the end of the trial, those in the intravenous treatment had a higher FVC% predicted compared to the oral group (MD 3.14%, 95% CI 0.31 to 5.97; high‐certainty evidence; Analysis 10.3). There was probably no difference in either serious or non‐serious adverse effects between the groups (moderate‐certainty evidence; Analysis 10.12) except there was a reduction in upper respiratory tract infections in the oral antibiotic treatment group (RR 6.37, 95% CI 1.44 to 28.21; moderate‐certainty evidence; Analysis 10.12).

Overall completeness and applicability of evidence

The aim of antibiotic therapy for early P aeruginosa infection in CF should be both successful and sustained eradication of the pathogen and improvement in (or slowing in the rate of decline of) clinical parameters, whilst minimising adverse effects and the isolation of new micro‐organisms. If P aeruginosa is successfully eradicated, but there is no measurable clinical benefit, it is likely that current measures of clinical status are not sufficiently sensitive or that the duration of follow‐up is too short to show a difference.

There are differences in the type and dose of drug administered to the treatment groups in the three placebo‐controlled trials of TNS (EARLY 2019; Gibson 2003; Wiesemann 1998). In the Wiesemann 1998 trial, tobramycin injectable solution was administered by nebuliser, at a low dose (80 mg twice daily) for a longer duration (12 months); whereas Gibson 2003 and EARLY 2019 used TSI TOBI^® (now marketed by Novartis) at a higher dose (300 mg twice daily) for a shorter duration (28 days). This is a potential source of heterogeneity between the trials.

Two trials included participants who were Pseudomonas‐naive and those that had not isolated P aeruginosa for at least six months (Proesmans 2013; Taccetti 2012), which is at variance with the 12‐month definition proposed by Lee to define a person as 'Pseudomonas‐free' (Lee 2003). We were not able to extract IPD for those participants who fit this longer definition of Pseudomonas‐free. The Treggiari 2011 trial required participants to have been free of P aeruginosa for at least two years. The TORPEDO 2020 trial also recruited those who were Pseudomonas‐naive; participants who had previously isolated P aeruginosa had to have been negative for at least 12 months.

The TORPEDO 2020 trial was the only trial using an intravenous therapy. The dose of oral ciprofloxacin used in those randomised to oral therapy was twice daily 15 mg/kg or 20 mg/kg (to a maximum of 750 mg) depending on age. This dose was broadly in keeping with previous trials (Proesmans 2013; Taccetti 2012; Treggiari 2011; Valerius 1991). The dose of inhaled colistimethate sodium was also broadly similar between these trials.

The ALPINE2 2017 trial was the only trial to use AZLI, and compared the efficacy of 14 days of AZLI followed by 14 days of placebo versus 28 days of AZLI. The primary endpoint was a negative respiratory culture 28‐days post‐treatment. Long‐term data were not presented. There was no comparison with another anti‐pseudomonal agent made.

Eradication of isolates of P aeruginosa is believed to be easier in people with CF with recent onset of infection, in particular in those who have non‐mucoid isolates of P aeruginosa. We could only include the first treatment period of the EARLY 2019 trial (which was a cross‐over trial). However, data from the second treatment period of this trial suggest that a 28‐day delay in initiating treatment for P aeruginosa substantially reduces the chance of successful eradication (from 76% to 48% success). Three trials included in this review recruited adults (Ratjen 2010; Taccetti 2012; TORPEDO 2020), suggesting that early P aeruginosa infection can be eradicated from adults as well as from children, and therefore adults should be included in future studies.

Most of the trials included in this review required patients to be clinically stable prior to recruitment. The results may not be applicable to people with CF who have a pulmonary exacerbation and simultaneously require eradication of P aeruginosa.

Finally, it should be noted that some of the trials were conducted between 10 and 20 years ago and the results may be less applicable to people with CF today, particularly following the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators into routine clinical care.

Quality of the evidence

The quality of the trials was variable, with important deficiencies identified in some. For example, in four out of the 11 included trials we judged there to be a high risk of bias from a lack of blinding of participants and clinicians; in two of these trials the different interventions used in the treatment and control groups precluded blinding (Proesmans 2013; Valerius 1991) and two trials were open‐label with no attempt made at blinding. We also judged there to be a high risk of bias due to selective reporting in three of the trials, which only reported summary statements with no actual data for a number of outcomes (Proesmans 2013; Ratjen 2010; Wiesemann 1998).

While we generally judged there to be a low risk of bias due to incomplete outcome data, there was incomplete follow‐up of a number of participants in one of the older and smaller trials (Wiesemann 1998). The absence of these data has complicated the combined analysis of the three trials that compare TNS with placebo (EARLY 2019; Gibson 2003; Wiesemann 1998); two trials were analysed on an intention‐to‐treat basis (EARLY 2019; Gibson 2003) and another on an available‐case basis (Wiesemann 1998). A sensitivity analysis based on best‐ and worst‐case scenarios demonstrated similar results to the available‐case analysis. The available‐case analysis revealed a reduction in the odds of a positive culture for P aeruginosa in the group treated with TNS when compared to the odds in the placebo group at both one and two months from the start of treatment (Wiesemann 1998). One trial only published limited results on a trial registry database; the limited information did not allow us to properly judge the risk of bias due to incomplete outcome data (ALPINE2 2017).

The Gibson 2003 trial was stopped early because of evidence of significant treatment effect. It has been suggested that the results of RCTs stopped early for benefit should be interpreted with caution, particularly when the number of events is small (Montori 2005).

In the Ratjen 2010 trial, the authors wished to enrol 120 participants in order to randomise 100 participants. They succeeded in recruiting 123 individuals, of whom 88 were randomised and 65 could be included in the analysis of the primary outcome (time to recurrence of P aeruginosa). This trial is potentially subject to bias because of the exclusion of non‐randomised individuals, including 31 people in whom there were elevated antibody titres to P aeruginosa.

The relationship between the presence of P aeruginosa in secretions from the upper respiratory tract and the isolation of P aeruginosa from the lower respiratory tract is inconsistent. Reporting of the presence of organisms in respiratory secretions is difficult to standardise, dependent on the sampling methods used and on the number of samples taken. The trials included in this review used a heterogeneous mix of methods to sample respiratory secretions from both the lower and upper respiratory tracts. No two trials used the same methods and more than one method was used in two trials. There was no subgroup analysis based on sampling method in any of the trials, probably owing to relatively small numbers of participants in individual trials. Wiesemann 1998 used a combination of oropharyngeal swabs and sputum samples, whereas Gibson 2003 used BAL fluid. Proesmans 2013 used sputum, throat swab and BAL. The Taccetti 2012 study did not describe the technique used for culture collection. The Treggiari 2011 trial enrolled younger children and used oropharyngeal swabs or sputum samples. The TORPEDO 2020 trial collected cough swabs from their younger participants and sputum samples (both induced and non‐induced) in older children. There were also a small number of samples taken from oropharyngeal aspirate (n = 1), nasopharyngeal aspirate (n = 1), cough plate (n = 9) and BAL (n = 3) (TORPEDO 2020). Armstrong 1996 has shown that the results of oropharyngeal specimens are poorly predictive of the presence of organisms in the lower respiratory tract. Valerius 1991 relied on sputum samples which can be of poor quality in younger children.

The certainty of evidence ranged from high to very low, based on GRADE criteria. We graded most evidence as moderate or low quality (see summary of findings Table 1 to summary of findings Table 10).

The main reasons for downgrading the certainty of evidence included risk of bias within the trials, as discussed above, but we also downgraded the certainty of evidence due to indirectness where the results were not applicable to all participants. This was mainly where trials included only adults or only children. We were not able to relate the results to the whole population to answer our review question. Five of our comparisons reported results only in children (summary of findings Table 1; summary of findings Table 2; summary of findings Table 5; summary of findings Table 7; summary of findings Table 8). We also downgraded the results where there was imprecision caused by wide CIs around the effect and small participant numbers, or both. Due to the fact that most of our comparisons included only one trial, there were limited opportunities to combine results in a meta‐analysis to increase the sample size and the certainty of the evidence. We also downgraded for imprecision where there were no numerical results available, and we were uncertain of the evidence provided by these trials.

Potential biases in the review process

The original review stated that trials would be included only where eradication begins within two months of isolation of P aeruginosa. In a post hoc change, this has now been altered to include those where eradication has been initiated up to six months since isolation. Whilst prompt treatment of new P aeruginosa infection is recommended (Smyth 2014), there is no robust evidence for a specific time limit for initiation of treatment.

The review now also includes two distinct groups of individuals ‐ those who are Pseudomonas‐naive and those who are Pseudomonas‐free.

Agreements and disagreements with other studies or reviews

We are not aware of any other studies or reviews which assess specific eradication treatment.

Figure 1

Study flow diagram.

Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Analysis 1.1

Comparison 1: Inhaled tobramycin (TNS) versus placebo, Outcome 1: Positive respiratory culture for P aeruginosa (300 mg 2x daily)

Analysis 1.2

Comparison 1: Inhaled tobramycin (TNS) versus placebo, Outcome 2: Positive respiratory culture for P aeruginosa (80 mg 2x daily)

Analysis 1.3

Comparison 1: Inhaled tobramycin (TNS) versus placebo, Outcome 3: Positive respiratory culture for P aeruginosa (combined available case analysis)

Analysis 1.4

Comparison 1: Inhaled tobramycin (TNS) versus placebo, Outcome 4: Positive respiratory culture for P aeruginosa (combined) ‐ best case

Analysis 1.5

Comparison 1: Inhaled tobramycin (TNS) versus placebo, Outcome 5: Positive respiratory culture for P aeruginosa (combined) ‐ worst case

Analysis 1.6

Comparison 1: Inhaled tobramycin (TNS) versus placebo, Outcome 6: Weight (kg) ‐ change from baseline

Analysis 1.7

Comparison 1: Inhaled tobramycin (TNS) versus placebo, Outcome 7: Adverse events

Analysis 1.8

Comparison 1: Inhaled tobramycin (TNS) versus placebo, Outcome 8: Modified Shwachmann score ‐ change from baseline

Analysis 2.1

Comparison 2: Inhaled tobramycin (TNS) 28 days versus 56 days, Outcome 1: Time to next isolation of P aeruginosa from BAL, sputum or oropharyngeal cultures

Analysis 2.2

Comparison 2: Inhaled tobramycin (TNS) 28 days versus 56 days, Outcome 2: Number of respiratory exacerbations

Analysis 2.3

Comparison 2: Inhaled tobramycin (TNS) 28 days versus 56 days, Outcome 3: Adverse events (up to 3 months)

Analysis 2.4

Comparison 2: Inhaled tobramycin (TNS) 28 days versus 56 days, Outcome 4: Adverse events (over 3 months)

Analysis 3.1

Comparison 3: Cycled inhaled tobramycin (TNS) versus culture‐based TNS, Outcome 1: Participants with one or more isolates of P aeruginosa from respiratory tract

Analysis 3.2

Comparison 3: Cycled inhaled tobramycin (TNS) versus culture‐based TNS, Outcome 2: FEV₁ % predicted ‐ change from baseline

Analysis 3.3

Comparison 3: Cycled inhaled tobramycin (TNS) versus culture‐based TNS, Outcome 3: Weight (kg) ‐ change from baseline

Analysis 3.4

Comparison 3: Cycled inhaled tobramycin (TNS) versus culture‐based TNS, Outcome 4: Height (cm) ‐ change from baseline

Analysis 3.5

Comparison 3: Cycled inhaled tobramycin (TNS) versus culture‐based TNS, Outcome 5: Time to severe pulmonary exacerbation

Analysis 3.6

Comparison 3: Cycled inhaled tobramycin (TNS) versus culture‐based TNS, Outcome 6: Participants with one or more severe pulmonary exacerbations

Analysis 3.7

Comparison 3: Cycled inhaled tobramycin (TNS) versus culture‐based TNS, Outcome 7: Time to pulmonary exacerbation (any severity)

Analysis 3.8

Comparison 3: Cycled inhaled tobramycin (TNS) versus culture‐based TNS, Outcome 8: Participants with one or more pulmonary exacerbations (any severity)

Analysis 3.9

Comparison 3: Cycled inhaled tobramycin (TNS) versus culture‐based TNS, Outcome 9: Participants with new isolates of Stenotrophomonas maltophilia

Analysis 3.10

Comparison 3: Cycled inhaled tobramycin (TNS) versus culture‐based TNS, Outcome 10: Participants with one or more serious adverse event

Analysis 4.1

Comparison 4: Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin (TNS), Outcome 1: Participants with one or more isolates of P aeruginosa from respiratory tract

Analysis 4.2

Comparison 4: Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin (TNS), Outcome 2: FEV₁ % predicted ‐ change from baseline

Analysis 4.3

Comparison 4: Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin (TNS), Outcome 3: Weight (kg) ‐ change from baseline

Analysis 4.4

Comparison 4: Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin (TNS), Outcome 4: Height (cm) ‐ change from baseline

Analysis 4.5

Comparison 4: Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin (TNS), Outcome 5: Time to severe pulmonary exacerbation

Analysis 4.6

Comparison 4: Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin (TNS), Outcome 6: Participants with one or more severe pulmonary exacerbations

Analysis 4.7

Comparison 4: Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin (TNS), Outcome 7: Time to pulmonary exacerbation (any severity)

Analysis 4.8

Comparison 4: Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin (TNS), Outcome 8: Participants with one of more pulmonary exacerbation (any severity)

Analysis 4.9

Comparison 4: Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin (TNS), Outcome 9: Participants with new isolates of Stenotrophomonas maltophilia

Analysis 4.10

Comparison 4: Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin (TNS), Outcome 10: Participants with one or more serious adverse event

Analysis 5.1

Comparison 5: Oral ciprofloxacin and inhaled colistin versus inhaled tobramycin (TNS), Outcome 1: Positive respiratory culture for P aeruginosa

Analysis 5.2

Comparison 5: Oral ciprofloxacin and inhaled colistin versus inhaled tobramycin (TNS), Outcome 2: Adverse events

Analysis 6.1

Comparison 6: Inhaled colistin plus oral ciprofloxacin versus inhaled tobramycin (TNS) plus oral ciprofloxacin, Outcome 1: Positive respiratory culture for P aeruginosa

Analysis 6.2

Comparison 6: Inhaled colistin plus oral ciprofloxacin versus inhaled tobramycin (TNS) plus oral ciprofloxacin, Outcome 2: FEV₁ % predicted (relative change from baseline)

Analysis 6.3

Comparison 6: Inhaled colistin plus oral ciprofloxacin versus inhaled tobramycin (TNS) plus oral ciprofloxacin, Outcome 3: Microbiology status (post‐trial)

Analysis 6.4

Comparison 6: Inhaled colistin plus oral ciprofloxacin versus inhaled tobramycin (TNS) plus oral ciprofloxacin, Outcome 4: Adverse events leading to trial discontinuation

Analysis 7.1

Comparison 7: Inhaled tobramycin (TNS) plus oral azithromycin versus TNS plus oral placebo, Outcome 1: Eradication of PA after first treatment quarter

Analysis 7.2

Comparison 7: Inhaled tobramycin (TNS) plus oral azithromycin versus TNS plus oral placebo, Outcome 2: Number of participants experiencing an exacerbation

Analysis 7.3

Comparison 7: Inhaled tobramycin (TNS) plus oral azithromycin versus TNS plus oral placebo, Outcome 3: Number of participants requiring additional antibiotics during the study

Analysis 7.4

Comparison 7: Inhaled tobramycin (TNS) plus oral azithromycin versus TNS plus oral placebo, Outcome 4: Number of hospitalisations

Analysis 7.5

Comparison 7: Inhaled tobramycin (TNS) plus oral azithromycin versus TNS plus oral placebo, Outcome 5: Isolation of other micro‐organisms at any time point post‐baseline

Analysis 7.6

Comparison 7: Inhaled tobramycin (TNS) plus oral azithromycin versus TNS plus oral placebo, Outcome 6: Adverse events

Analysis 8.1

Comparison 8: Oral ciprofloxacin and inhaled colistin versus no treatment, Outcome 1: Proportion colonised with P aeruginosa

Analysis 9.1

Comparison 9: AZLI 14 days plus placebo 14 days versus AZLI 28 days, Outcome 1: Proportion of participants with negative cultures at 28 days

Analysis 9.2

Comparison 9: AZLI 14 days plus placebo 14 days versus AZLI 28 days, Outcome 2: Adverse Events

Analysis 10.1

Comparison 10: IV ceftazidime with tobramycin versus oral ciprofloxacin, Outcome 1: Eradication of P aeruginosa from respiratory samples at 3 months and remaining free

Comparison 10: IV ceftazidime with tobramycin versus oral ciprofloxacin, Outcome 2: FEV1 % predicted

Analysis 10.2

Comparison 10: IV ceftazidime with tobramycin versus oral ciprofloxacin, Outcome 2: FEV₁ % predicted

Analysis 10.3

Comparison 10: IV ceftazidime with tobramycin versus oral ciprofloxacin, Outcome 3: FVC % predicted

Analysis 10.4

Comparison 10: IV ceftazidime with tobramycin versus oral ciprofloxacin, Outcome 4: FEF_25-75

Analysis 10.5

Comparison 10: IV ceftazidime with tobramycin versus oral ciprofloxacin, Outcome 5: Growth and nutritional status: height‐for‐age z score

Analysis 10.6

Comparison 10: IV ceftazidime with tobramycin versus oral ciprofloxacin, Outcome 6: Growth and nutritional status: weight‐for‐age z score

Analysis 10.7

Comparison 10: IV ceftazidime with tobramycin versus oral ciprofloxacin, Outcome 7: Growth and nutritional status: BMI z score (paediatric)

Comparison 10: IV ceftazidime with tobramycin versus oral ciprofloxacin, Outcome 8: Growth and nutritional status: BMI (kg/m2; adult)

Analysis 10.8

Comparison 10: IV ceftazidime with tobramycin versus oral ciprofloxacin, Outcome 8: Growth and nutritional status: BMI (kg/m²; adult)

Analysis 10.9

Comparison 10: IV ceftazidime with tobramycin versus oral ciprofloxacin, Outcome 9: Frequency of exacerbations: number of participants who experienced an exacerbation

Analysis 10.10

Comparison 10: IV ceftazidime with tobramycin versus oral ciprofloxacin, Outcome 10: Frequency of exacerbations: number of participants admitted to hospital

Analysis 10.11

Comparison 10: IV ceftazidime with tobramycin versus oral ciprofloxacin, Outcome 11: Isolation of other organisms: number of participants isolating a positive culture during 15‐month study period

Analysis 10.12

Comparison 10: IV ceftazidime with tobramycin versus oral ciprofloxacin, Outcome 12: Adverse events

Summary of findings 1. Inhaled tobramycin (TNS) compared with placebo

Outcomes		*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (trials)	Certainty of the evidence (GRADE)	Comments
*Inhaled tobramycin (TNS) compared with placebo for eradicating Pseudomonas aeruginosa* in people with cystic fibrosis**
Patient or population: adults and children with cystic fibrosis and a positive microbiological isolate of Pseudomonas aeruginosa from a respiratory tract specimen Settings: outpatients Intervention: TNS Comparison: placebo
		Assumed risk	Corresponding risk
		Placebo	TNS
*Eradication of P aeruginosa* from the respiratory tract*: proportion with positive respiratory culture for P aeruginosa* Follow‐up: up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months (1 month)	787 per 1000	182 per 1000 (69 to 400 per 1000)	OR 0.06 (95% CI 0.02 to 0.18)	89 (3 RCTs)	⊕⊕⊝⊝ low^a,b	The included trials gave very different doses of TNS (80 mg or 300 mg 2 x daily).
	Follow‐up: 6 to 24 months after onset of treatment (12 months)	OR 0.02 (95% CI 0.00 to 0.67)		OR 0.02 (95% CI 0.00 to 0.67)	12 (1 RCT)	⊕⊝⊝⊝ very low^a,b,c	We were unable to calculate assumed and corresponding risk as all the participants in the placebo group had a positive respiratory culture at 12 months. Results of different time points and sensitivity analyses to account for missing data in 1 trial were variable, showing no consistent advantage to TNS over placebo.
FEV₁ Follow‐up: up to 2 years		There were no changes in spirometric pulmonary function during or after the treatment period.		NR	up to 22^d (1 RCT)	⊕⊝⊝⊝ very low^a,b,e	No numerical data were reported.
FVC Follow‐up: up to 2 years		There were no changes in spirometric pulmonary function during or after the treatment period.		NR	up to 22^d (1 RCT)	⊕⊝⊝⊝ very low^a,b,e	No numerical data were reported.
Growth and nutritional status: change in weight (kg) from baseline Follow‐up: up to 2 years		Outcome not reported at specified time point (see comments).					There was no difference in the mean change in weight from baseline between groups at 1 month (MD 0.20 kg, 95% CI ‐0.28 to 0.68) or 2 months (0.1 kg, 95% CI ‐0.38 to 0.58).
Frequency of infective pulmonary exacerbations: number of exacerbations per patient year		Outcome not reported.
Isolation of other micro‐organisms from the respiratory tract: number of positive cultures per patient year Follow‐up: up to 2 years		Outcome not reported at specified time point (see comments)					No numerical data were reported. At the 2‐month time point, there were no changes in the prevalence of other micro‐organisms, including multiresistant organisms, cultured from respiratory secretions.
Adverse effects of antibiotics: participants experiencing cough Follow‐up: up to 2 years		342 per 1000	283 per 1000 (49 to 750)	OR 0.76 (0.10 to 5.77)	72 (2 RCTs)	⊕⊝⊝⊝ very low^a,b,c	No other specific adverse events were reported. The trial reporting at 2 months found no difference between groups with regard to cough (OR 0.58, 95% CI 0.03 to 10.86), serum creatinine levels or auditory threshold at the 2‐month time point.
The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FEV₁: forced expiratory volume in one second; FVC: forced vital capacity; MD: mean difference; NA: not applicable; NR: not reported OR: odds ratio; P aeruginosa: Pseudomonas aeruginosa*; RCT: randomised controlled trial; TNS: inhaled tobramycin
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded once due to risk of bias; methodological information was limited and unclear in the included trials and there were concerns regarding incomplete outcome data, selective reporting and other biases due to the early termination of one trial. ^bDowngraded once due to applicability: the included trials recruited only children; results are not applicable to adults. ^cDowngraded once due to imprecision caused by very small sample size and wide CIs. ^dIn the included trial, 22 participants were randomised, but it is not clear if all participants contributed to this outcome. ^eDowngraded once due to imprecision: no numerical results available.

Summary of findings 1. Inhaled tobramycin (TNS) compared with placebo

Summary of findings 2. Inhaled tobramycin (TNS) (28 days) compared with TNS (56 days)

Outcomes		*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
*Inhaled tobramycin (TNS) (28 days) compared with TNS (56 days) for eradicating Pseudomonas aeruginosa* in people with cystic fibrosis**
Patient or population: adults and children with cystic fibrosis and a positive microbiological isolate of P aeruginosa from a respiratory tract specimen Settings: outpatients Intervention: TNS (28 days) Comparison: TNS (56 days)
		Assumed risk	Corresponding risk
		TNS (56 days)	TNS (28 days)
*Eradication of P aeruginosa* from the respiratory tract:** time to next isolation of P aeruginosa from BAL, sputum or oropharyngeal cultures Follow‐up: up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months	Not reported at this time point
	Follow‐up: 6 to 24 months after onset of treatment	By 26.12 months, 50% of people in the 56‐day group can expect to have experienced a recurrence of P aeruginosa.	By 25.18 months, 50% of people in the 28‐day group can expect to have experienced a recurrence of P aeruginosa.	HR 0.81 (95% CI 0.37 to 1.76)	65^a (1 RCT)	⊕⊕⊝⊝ low^b,c
FEV₁: % predicted Follow‐up: 6 to 24 months (N.B. this trial reported at 27 months)		There were no major short‐ or long‐term changes in spirometric parameters were observed during the trial period.		NR	up to 88^a (1 RCT)	⊕⊝⊝⊝ very low^b,c,d	Changes in lung function were not reported separately for each treatment arm.
FVC: % predicted Follow‐up: 6 to 24 months (N.B. this trial reported at 27 months)		There were no major short‐ or long‐term changes in spirometric parameters were observed during the trial.		NR	up to 88^a (1 RCT)	⊕⊝⊝⊝ very low^b,c,d	Changes in lung function were not reported separately for each treatment arm.
Growth and nutritional status: weight, height and BMI Follow‐up: 6 to 24 months		No differences in weight, height or body mass index were reported.		NR	up to 88^a (1 RCT)	⊕⊝⊝⊝ very low^b,c,d	Numerical data were not reported or comparative results across the treatment groups.
Frequency of infective pulmonary exacerbations: number of exacerbations per patient year Follow‐up: 6 to 24 months (N.B. this trial reported at 27 months)		47 per 1000	9 per 1000 (0 to 188 per 1000)	OR 0.19 (95% CI 0.01 to 4.00)	77^a (1 RCT)	⊕⊝⊝⊝ very low^b,c,e
Isolation of other micro‐organisms from the respiratory tract: number of positive cultures per patient year Follow‐up: 6 to 24 months (N.B. this trial reported at 27 months)		There were no consistent trends reported in the isolation of non‐P aeruginosa organisms (one isolate only of Stenotrophomonas maltophilia, which was seen in the 28‐day arm).		NR	up to 88^a (1 RCT)	⊕⊝⊝⊝ very low^b,c,d	Numerical data were not reported, or comparative results across the treatment groups.
Adverse effects of antibiotics Follow‐up: 6 to 24 months (N.B. this trial reported at 27 months)		There were no differences between treatment groups in terms of any reported adverse events at any time point.		NA	up to 77^a (1 RCT)	⊕⊝⊝⊝ very low^b,c,f
The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BAL: bronchial lavage CI: confidence interval; FEV₁: forced expiratory volume in 1 second; FVC: forced vital capacity; HR: hazard ratio; NA: not applicable; NR: not reported OR: odds ratio; P aeruginosa: Pseudomonas aeruginosa*; RCT: randomised controlled trial; TNS: inhaled tobramycin.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aIn the included trial, 88 participants were randomised but not all participants contributed to all outcomes (unclear how many participants contributed to some outcomes). ^bDowngraded once due to risk of bias; methodological information was limited and unclear in the included trial and there were concerns of bias due to selective reporting of results and lack of blinding. ^cDowngraded once due to applicability: the included trials recruited only children; results are not applicable to adults. ^dDowngraded once due to imprecision: no numerical comparative results available. ^eDowngraded once due to imprecision: very wide CIs around the effect size ^fDowngraded once due to imprecision: some wide confidence intervals around effects sizes (small event rates) and a lot of adverse events analysed increasing the statistical chance of a spurious finding.

Summary of findings 2. Inhaled tobramycin (TNS) (28 days) compared with TNS (56 days)

Summary of findings 3. Cycled inhaled tobramycin (TNS) compared to culture‐based TNS

Outcomes		*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
*Cycled inhaled tobramycin (TNS) compared to culture‐based TNS for eradicating Pseudomonas aeruginosa* in people with cystic fibrosis**
Patient or population: adults and children with cystic fibrosis and a positive microbiological isolate of P aeruginosa from a respiratory tract specimen Settings: outpatients Intervention: cycled TNS Comparison: culture‐based TNS
		Assumed risk	Corresponding risk
		Culture‐based inhaled tobramycin	Cycled inhaled tobramycin
*Eradication of P aeruginosa* from the respiratory tract:** proportion of participants with one or more isolates of P aeruginosa from the respiratory tract Follow‐up: up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months	Outcome not reported at this time point.
	Follow‐up: 6 to 24 months after onset of treatment	467 per 1000	228 per 1000 (145 to 383 per 1000)	OR 0.51 (95% CI 0.31 to 0.82)	298^a (1 RCT)	⊕⊕⊕⊝ moderate^b	The original trial report published age group–adjusted ORs, which are slightly different to the results of this review.
FEV₁: mean 70‐week % change in FEV₁ (% predicted) Follow‐up: 70 weeks		The mean 70‐week % change in FEV₁ (% predicted) was ‐1.61% in the culture‐based TNS group.	The mean 70‐week % change in FEV₁ (% predicted) was 2.38% higher (2% lower to 6.76% higher) in the cycle‐based TNS group.	NA	143^a (1 RCT)	⊕⊕⊝⊝ low^b,c
FVC		Outcome not reported.		NA	NA	NA
Growth and nutritional status: mean 70‐week change from baseline in weight (kg) and height (cm) Follow‐up: 70 weeks		The mean 70‐week change in weight (kg) in the culture‐based group was 3.9kg. Change in weight in the cycled group was 0.10kg higher (0.47 lower to 0.67 higher). The mean 70‐week change in height (cm) in the culture‐based group was 9.4cm. Change in height in the cycled group was 0.20cm lower (0.86 lower to 0.46 higher).		NA	304^a (1 RCT)	⊕⊕⊕⊝ moderate^b
Frequency of infective pulmonary exacerbations: proportion of participants with one or more pulmonary exacerbations (any severity) Follow‐up: 18 months		533 per 1000	400 per 1000 (256 to 624 per 1000)	OR 0.75 (95% 0.48 to 1.17)	304^a (1 RCT)	⊕⊕⊕⊝ moderate^b	There was also no difference between groups in terms of proportion of participants with 1 or more severe pulmonary exacerbation or in terms of time to pulmonary exacerbation (severe or any severity).
Isolation of other micro‐organisms from the respiratory tract: proportion of participants with new isolates of Stenotrophomonas maltophilia Follow‐up: 18 months		184 per 1000	217 per 1000 (118 to 390 per 1000)	OR 1.18 (95% CI 0.65 to 2.12)	279^a (1 RCT)	⊕⊕⊕⊝ moderate^b
Adverse effects of antibiotics: proportion of participants with one or more serious adverse events Follow‐up: 18 months		289 per 1000	246 per 1000 (147 to 405 per 1000)	OR 0.85 (95% 0.51 to 1.40)	304^a (1 RCT)	⊕⊕⊕⊝ moderate^b
The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FEV₁: forced expiratory volume in 1 second; FVC: forced vital capacity; NA: not applicable; NR: not reported OR: odds ratio; P aeruginosa: Pseudomonas aeruginosa*; RCT: randomised controlled trial; TNS: inhaled tobramycin.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aIn the included trial, 306 participants were randomised, 304 received treatment but not all participants contributed to all outcomes (unclear how many participants contributed to some outcomes, spirometry not performed in very young children (less than 4 years of age)). ^bDowngraded once due to applicability: the included trial recruited only children; results are not applicable to adults. Also, the included trial required participants to have been free of P aeruginosa for at least 2 years, so results may not be applicable to a wider population. ^cDowngraded once due to applicability: a large proportion of the randomised and treated participants (161 out of 304, 53%) did not contribute to this outcome.

Summary of findings 3. Cycled inhaled tobramycin (TNS) compared to culture‐based TNS

Summary of findings 4. Ciprofloxacin compared to placebo added to cycled and culture‐based inhaled tobramycin (TNS) therapy

Outcomes		*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
*Ciprofloxacin compared to placebo added to cycled and culture‐based inhaled tobramycin (TNS) therapy for eradicating Pseudomonas aeruginosa* in people with cystic fibrosis**
Patient or population: adults and children with cystic fibrosis and a positive microbiological isolate of P aeruginosa from a respiratory tract specimen Settings: outpatients Intervention: ciprofloxacin added to cycled and culture‐based TNS therapy Comparison: placebo added to cycled and culture‐based TNS therapy
		Assumed risk	Corresponding risk
		Placebo added to cycled and culture‐based TNS therapy	Ciprofloxacin added to cycled and culture‐based TNS therapy
*Eradication of P aeruginosa* from the respiratory tract:** proportion of participants with one or more isolates of P aeruginosa from the respiratory tract Follow‐up: up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months	Outcome not reported at this time point.
	Follow‐up: 6 to 24 months after onset of treatment	362 per 1000	322 per 1000 (199 to 521 per 1000)	OR 0.89 (95% CI 0.55 to 1.44)	298^a (1 RCT)	⊕⊕⊕⊝ moderate^b	The original trial report published age group‐adjusted ORs, which are slightly different to the results of this review.
FEV₁: mean 70‐week % change in FEV₁ (% predicted) Follow‐up: 70 weeks		The mean 70‐week % change in FEV₁ (% predicted) was ‐1.85% in the placebo added to cycled and culture‐based TNS therapy group.	The mean 70‐week % change in FEV₁ (% predicted) was 3.02% higher (1.33% lower to 7.37% higher) in the ciprofloxacin added to cycled and culture‐based TNS therapy group.	NA	143^a (1 RCT)	⊕⊕⊝⊝ low^b,c
FVC		Outcome not reported.		NA	NA	NA
Growth and nutritional status: mean 70‐week change from baseline in weight (kg) and height (cm) Follow‐up: 70 weeks		The mean 70‐week change in weight (kg) in the placebo added to cycled and culture‐based therapy group was 4.10 kg. Change in weight in the cycled group was 0.30 kg lower (0.88 lower to 0.28 higher). The mean 70‐week change in height (cm) in the placebo added to cycled and culture‐based therapy group was 9.4 cm. Change in height in the cycled group was 0.20 cm lower (0.86 lower to 0.46 higher).		NA	304^a (1 RCT)	⊕⊕⊕⊝ moderate^b
Frequency of infective pulmonary exacerbations: proportion of participants with one or more pulmonary exacerbations (any severity) Follow‐up: 18 months		447 per 1000	666 per 1000 (425 to 1000)	OR 1.49 (95% CI 0.95 to 2.33)	304^a (1 RCT)	⊕⊕⊕⊝ moderate^b	There was also no difference between groups in the proportion of participants with 1 or more severe pulmonary exacerbations or in the time to pulmonary exacerbation (severe or any severity).
Isolation of other micro‐organisms from the respiratory tract: proportion of participants with new isolates of Stenotrophomonas maltophilia Follow‐up: 18 months		183 per 1000	220 per 1000 (121 to 395 per 1000)	OR 1.20 (95% CI 0.66 to 2.16)	279^a (1 RCT)	⊕⊕⊕⊝ moderate^b
Adverse effects of antibiotics: proportion of participants with one or more serious adverse event Follow‐up: 18 months		230 per 1000	354 per 1000 (214 to 591 per 1000)	OR 1.54 (95% CI 0.93 to 2.57)	304^a (1 RCT)	⊕⊕⊕⊝ moderate^b
The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FEV₁: forced expiratory volume in one second; FVC: forced vital capacity; NA: not applicable; NR: not reported; OR: odds ratio; P aeruginosa: Pseudomonas aeruginosa*; RCT: randomised controlled trial; TNS: inhaled tobramycin.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aIn the included trial, 306 participants were randomised, 304 received treatment but not all participants contributed to all outcomes (unclear how many participants contributed to some outcomes, spirometry not performed in very young children (less than 4 years of age)). ^bDowngraded once due to applicability: the included trial recruited only children; results are not applicable to adults. Also, the included trial required participants to have been free of P aeruginosa for at least 2 years, so results may not be applicable to a wider population. ^cDowngraded once due to applicability: a large proportion of the randomised and treated participants (161 out of 304, 53%) did not contribute to this outcome.

Summary of findings 4. Ciprofloxacin compared to placebo added to cycled and culture‐based inhaled tobramycin (TNS) therapy

Summary of findings 5. Oral ciprofloxacin and inhaled colistin compared to inhaled tobramycin (TNS)

Outcomes		*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
*Oral ciprofloxacin and inhaled colistin compared to inhaled tobramycin for eradicating Pseudomonas aeruginosa* in people with cystic fibrosis**
Patient or population: adults and children with cystic fibrosis and a positive microbiological isolate of P aeruginosa from a respiratory tract specimen Settings: outpatients Intervention: oral ciprofloxacin and inhaled colistin Comparison: TNS
		Assumed risk	Corresponding risk
		TNS	Oral ciprofloxacin and inhaled colistin
*Eradication of P aeruginosa* from the respiratory tract:** proportion with positive respiratory culture for P aeruginosa Follow‐up: up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months	552 per 1000	346 per 1000	OR 0.43 (95% CI 0.15 to 1.23)	Up to 58^a (1 RCT)	⊕⊝⊝⊝ very low^b,c,d
	Follow‐up: 6 to 24 months after onset of treatment	458 per 1000	348 per 1000 (110 to 1000 per 1000)	OR 0.76 (95% CI 0.24 to 2.42)	Up to 58^a (1 RCT)	⊕⊝⊝⊝ very low^b,c,d
FEV₁: change from baseline (% predicted) Follow‐up: over 6 months and up to 24 months		Median change from baseline in FEV₁ (% predicted) for all the participants was ‐1%.		NR	Up to 58^a (1 RCT)	⊕⊝⊝⊝ very low^b,c,e	Changes in FEV₁ were not reported separately for each treatment arm.
FVC Follow‐up: NA		Outcome not reported.		NA	NA	NA
Growth and nutritional status: BMI and weight z score Follow‐up: 6 to 24 months		Both BMI z score and weight z score were reported not to have changed significantly for trial participants as a whole.		NR	Up to 58^a (1 RCT)	⊕⊝⊝⊝ very low^b,c,e	Numerical data were not reported for comparative results across the treatment groups.
Frequency of infective pulmonary exacerbations: number of exacerbations per patient year Follow‐up: over 6 months and up to 24 months		During the first 6 months of follow‐up, there was no difference between the 2 treatment arms in number of oral antibiotic treatment days.		NR	Up to 58^a (1 RCT)	⊕⊝⊝⊝ very low^b,c,e	These oral antibiotics were given for symptoms and not because of failed eradication. No numerical data were reported.
Isolation of other micro‐organisms from the respiratory tract: number of positive cultures per patient year Follow‐up: NA		Outcome not reported.		NA	NA	NA
Adverse effects of antibiotics: severe cough Follow‐up: over 6 months and up to 24 months		34 per 1000	11 per 1000 (0 to 280 per 1000)	OR 0.32 (95% CI 0.01 to 8.24)	Up to 58^a (1 RCT)	⊕⊝⊝⊝ very low^b,c,d	No other specific adverse events were reported.
The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BMI: body mass index; CI: confidence interval; FEV₁: forced expiratory volume in one second; FVC: forced vital capacity; NA: not applicable; NR: not reported OR: odds ratio; P aeruginosa: Pseudomonas aeruginosa*; RCT: randomised controlled trial; TNS: inhaled tobramycin.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aIn the included trial, 58 participants were randomised but not all participants contributed to all outcomes (unclear how many participants contributed to some outcomes). ^bDowngraded once due to risk of bias; methodological information was limited and unclear in the included trial and there were concerns of bias due to selective reporting of results. ^cDowngraded once due to applicability: the included trials recruited only children; results are not applicable to adults. ^dDowngraded once due to imprecision: very wide CIs around the effect size. ^eDowngraded once due to imprecision: no numerical comparative results available.

Summary of findings 5. Oral ciprofloxacin and inhaled colistin compared to inhaled tobramycin (TNS)

Summary of findings 6. Inhaled colistin plus oral ciprofloxacin compared to inhaled tobramycin (TNS) plus oral ciprofloxacin

Outcomes		*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
*Inhaled colistin plus oral ciprofloxacin compared to inhaled tobramycin (TNS) plus oral ciprofloxacin for eradicating Pseudomonas aeruginosa* in people with cystic fibrosis**
Patient or population: adults and children with cystic fibrosis and a positive microbiological isolate of P aeruginosa from a respiratory tract specimen Settings: outpatients Intervention: inhaled colistin plus oral ciprofloxacin Comparison: TNS plus oral ciprofloxacin
		Assumed risk	Corresponding risk
		TNS plus oral ciprofloxacin	Inhaled colistin plus oral ciprofloxacin
*Eradication of P aeruginosa* from the respiratory tract:** proportion with positive respiratory culture for P aeruginosa Follow‐up: up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months	347 per 1000	371 per 1000 (254 to 506	OR 1.11 (95% CI 0.64 to 1.92)	Up to 223^a (1 RCT)	⊕⊕⊝⊝ low^b,c
	Follow‐up: 6 to 24 months after onset of treatment (median 16 months)	315 per 1000	403 per 1000 (227 to 721 per 1000)	OR 1.28 (95% CI 0.72 to 2.29)	Up to 223^a (1 RCT)	⊕⊕⊝⊝ low^b,c
FEV₁: relative change in % predicted FEV₁ from baseline		Outcome not reported at specified time point.					After a mean time of 54 days there was no difference in mean relative change in FEV1 % predicted between groups, MD ‐2.40 (95% CI ‐5.89 to 1.09)
FVC Follow‐up: NA		Outcome not reported.
Growth and nutritional status Follow‐up: NA		Outcome not reported.
Frequency of infective pulmonary exacerbations: number of exacerbations per patient year Follow‐up: NA		Outcome not reported.
Isolation of other micro‐organisms from the respiratory tract: number of positive cultures per patient year Follow‐up: median 16 months		There were no differences during follow‐up between the two groups for isolation of: Stenotrophomonas maltophilia (OR 0.89 (95% CI 0.45 to 1.78)) ,Achromobacter xylosoxidans (OR 1.53 (95% CI 0.51 to 4.57))or Aspergillus species (OR 0.48 (95% CI 0.21 to 1.07)).		NA	205^a (1 RCT)	⊕⊕⊕⊝ moderate^b
Adverse effects of antibiotics: leading to trial discontinuation Follow‐up: median 16 months		21 out of 118 (18%) participants discontinued the trial early due to adverse events in the TNS plus oral ciprofloxacin group.	17 out of 105 (16%) participants discontinued the trial early due to adverse events in the inhaled colistin plus oral ciprofloxacin group.	NA	223 (1 RCT)	⊕⊕⊕⊝ moderate^b	Reasons for discontinuations included vomiting, photosensitivity, wheeze and pulmonary exacerbation.
The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FEV₁: forced expiratory volume in one second; FVC: forced vital capacity; NA: not applicable; NR: not reported OR: odds ratio; P aeruginosa: Pseudomonas aeruginosa*; RCT: randomised controlled trial; TNS: inhaled tobramycin.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aIn the included trial, 223 participants were randomised but not all participants contributed to all outcomes (unclear how many participants contributed to some outcomes, spirometry not performed in very young children). ^bDowngraded once due to risk of bias; methodological information was limited and unclear in the included trial and there were potential concerns of bias due to selective reporting of results and lack of blinding. ^cDowngraded once due to imprecision: wide CIs around the effect size.

Summary of findings 6. Inhaled colistin plus oral ciprofloxacin compared to inhaled tobramycin (TNS) plus oral ciprofloxacin

Summary of findings 7. Inhaled tobramycin (TNS) plus oral azithromycin compared to TNS plus oral placebo

Outcomes		*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
*Inhaled tobramycin (TNS) plus oral azithromycin compared to TNS plus oral placebo for eradicating Pseudomonas aeruginosa* in people with cystic fibrosis**
Patient or population: children with cystic fibrosis and a new culture positive for P aeruginosa Settings: outpatients Intervention: TNS plus oral azithromycin Comparison: TNS plus oral placebo
		Assumed risk	Corresponding risk
		TNS plus placebo	TNS plus azithromycin
*Eradication of P aeruginosa* from the respiratory tract:** number of participants eradicated after three month treatment phase Follow‐up: up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months (3 months)	667 per 1000	674 per 1000 (500 to 900 per 1000)	RR 1.01 (0.75 to 1.35)	91 (1 RCT)	⊕⊕⊝⊝ low^a,b	This included participants who were positive for P aeruginosa at baseline and had a culture result available at the end of the first treatment quarter.
	Follow‐up: 6 to 24 months after onset of treatment	Outcome not reported at this time point.
FEV_1: mean change in FEV₁ % predicted Follow‐up: 18 months		There was no difference in the mean change in FEV₁ over the 18‐month period between groups, MD ‐1.71% (‐7.76 to 4.34).			132 (1 RCT)	⊕⊕⊝⊝ low^a,b	P = 0.384 Results taken directly from paper.
FVC: mean change in FVC % predicted Follow‐up: 18 months		There was no difference in the mean change in FVC over the 18‐month period between groups.				⊕⊕⊝⊝ low^a,b	No data are available for this outcome.
Growth and nutritional status: mean change in weight (kg) from baseline Follow‐up: 18 months		There was a slight improvement in weight in the azithromycin group compared to the placebo group, MD 1.27 (0.01 to ‐2.52)			221 (1 RCT)	⊕⊕⊕⊝ moderate^b	P = 0.046 Results taken directly from paper.
Frequency of infective pulmonary exacerbations: number of participants experiencing an exacerbation by the end of the study Follow‐up: 18 months		522 per 1000	392 per 1000 (292 to 522 per 1000)	RR 0.75 (0.56 to 1.00)	221 (1 RCT)	⊕⊕⊕⊝ moderate^b
Isolation of other micro‐organisms from the respiratory tract: number of participants with a positive result for other organisms. Follow‐up: 18 months		The emergence of other pathogens (including A xylosoxidans, B cepacia, H influenzae, S aureus, S maltophilia and NTM) was comparable between groups and numbers were low.			221 (1 RCT)	⊕⊕⊕⊝ moderate^b	The analysis included participants with a positive result who were negative at baseline.
Adverse effects of antibiotics: number of participants experiencing any adverse event Follow‐up: 18 months		883 per 1000	927 per 1000 (848 to 1000 per 1000)	RR 1.05 (0.96 to 1.14)	221 (1 RCT)	⊕⊕⊕⊝ moderate^b	There was no difference between groups in the occurrence of adverse events, including serious adverse events.
The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). A xylosoxidans: Achromobacter xylosoxidans;B cepacia: Burkholderia cepacia; CI: confidence interval; FEV₁: forced expiratory volume in 1 second; FVC: forced vital capacity; H influenzae: Haemophilus influenzae; MD: mean difference; NA: not applicable; NR: not reported; NTM: nontuberculous mycobacterium; OR: odds ratio; P aeruginosa: Pseudomonas aeruginosa; RCT: randomised controlled trial; RR: risk ratio; S aureus: Staphylococcus aureus; S maltophilia: Stenotrophomonas maltophilia;* TNS: inhaled tobramycin.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded once due to imprecision: small number of participants. ^bDowngraded once due to indirectness: the included trial recruited only children; results are not applicable to adults.

Summary of findings 7. Inhaled tobramycin (TNS) plus oral azithromycin compared to TNS plus oral placebo

Summary of findings 8. Oral ciprofloxacin and inhaled colistin compared with no treatment

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
*Oral ciprofloxacin and inhaled colistincompared with no treatment for eradicating Pseudomonas aeruginosa* in people with cystic fibrosis**
Patient or population: adults and children with cystic fibrosis and a positive microbiological isolate of P aeruginosa from a respiratory tract specimen Settings: outpatients Intervention: oral ciprofloxacin and inhaled colistin Comparison: no treatment
	Assumed risk	Corresponding risk
	No treatment	Oral ciprofloxacin and inhaled colistin
*Eradication of P aeruginosa* from the respiratory tract**	Outcome not reported.
FEV₁	Outcome not reported.
FVC	Outcome not reported.
Growth and nutritional status	Outcome not reported.
Frequency of infective pulmonary exacerbations: number of exacerbations per patient year	Outcome not reported.
Isolation of other micro‐organisms from the respiratory tract: number of positive cultures per patient year	Outcome not reported.
Adverse effects of antibiotics Follow‐up: 27 months	No adverse effects were reported in either group.		NR	26 (1 RCT)	⊕⊝⊝⊝ very low^a,b,c	No numerical data were reported.
The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FEV₁: forced expiratory volume in one second; FVC: forced vital capacity; NA: not applicable; NR: not reported; P aeruginosa: Pseudomonas aeruginosa*; RCT: randomised controlled trial.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded once due to risk of bias; methodological information was limited and unclear in the included trial and there was a high risk of bias due to lack of blinding. ^bDowngraded once due to applicability: the included trial recruited only children; results are not applicable to adults. ^cDowngraded once due to imprecision: no numerical results available.

Summary of findings 8. Oral ciprofloxacin and inhaled colistin compared with no treatment

Summary of findings 9. 14 days inhaled AZLI plus 14 days placebo compared to 28 days inhaled AZLI

Outcomes		*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
*Inhaled AZLI 14 days followed by placebo 14 days compared with AZLI 28 days for eradicating Pseudomonas aeruginosa* in people with cystic fibrosis**
Patient or population: children and adolescents with cystic fibrosis Settings: not stated Intervention: 14 days of AZLI followed by 14 days of placebo Comparison: 28 days of AZLI
		Assumed risk	Corresponding risk
		AZLI 28 days	AZLI 14 days plus placebo 14 days
*Eradication of P aeruginosa* from the respiratory tract: proportion of participants with a negative culture for PA during the 28 days following treatment Follow‐up:** up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months (28 days)	The proportion of participants with a negative culture was 63.4% (51.97).	The proportion of participants with a negative culture was 7.50% lower in the AZLI 14 group than the AZLI 28 group (24.80% lower to 9.80% higher).	NA	139 (1 RCT)	⊕⊝⊝⊝ very low^a,b,c
	Follow‐up: 6 to 24 months after onset of treatment	Outcome not reported at this time point
FEV₁ % predicted		This outcome was not reported.
FVC % predicted		This outcome was not reported.
Growth and nutritional status		This outcome was not reported.
Frequency of infective pulmonary exacerbations		This outcome was not reported.
Isolation of other micro‐organisms from the respiratory tract		This outcome was not reported.
Adverse effects of antibiotics: number of participants reporting a serious adverse event		Outcome not reported at this time point.					Adverse events were reported at the 28‐day time point. There was no difference in serious adverse events between groups, RR 1.27 (95% CI 0.35 to 4.53)
The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AZLI: aztreonam lysine; CI: confidence interval; FEV₁: forced expiratory volume in 1 second; FVC: forced vital capacity; P aeruginosa: Pseudomonas aeruginosa*; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded once due to unclear risk of bias, particularly around randomisation and allocation concealment. The trial was described as randomised but no further details were given. ^bDowngraded once due to imprecision from a small number of participants. ^cDowngraded once due to indirectness as the trial was only conducted in children and adolescents. It is unclear whether the results would be reproducible in an adult population.

Summary of findings 9. 14 days inhaled AZLI plus 14 days placebo compared to 28 days inhaled AZLI

Summary of findings 10. Intravenous ceftazidime with tobramycin compared with oral ciprofloxacin

Outcomes		*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
*Intravenous ceftazidime with tobramycin compared with oral ciprofloxacin for eradicating Pseudomonas aeruginosa* in people with cystic fibrosis**
Patient or population: adults and children with cystic fibrosis and a positive microbiological isolate of Pseudomonas aeruginosa from a respiratory tract specimen Settings: outpatients Intervention: IV ceftazidime with tobramycin Comparison: oral ciprofloxacin
		Assumed risk	Corresponding risk
		Oral ciprofloxacin	IV ceftazidime
*Eradication of P aeruginosa* from the respiratory tract:** number of participants testing negative for P aeruginosa at 3 months and remaining free until 15 months Follow‐up: up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months	Outcome not reported at this time point					The primary outcome was the proportion of participants who were successfully eradicated at 3 months and remained free at 15 months.
	Follow‐up: 6 to 24 months after onset of treatment (15 months)	523 per 1000	439 per 1000 (340 to 570 per 1000)	RR 0.84 (0.65 to 1.09)	255 (1 RCT)	⊕⊕⊕⊕ high^a	30 participants were excluded from the primary analysis as they did not have a sample taken at 5 months. Further sensitivity analyses confirmed the same results.
FEV₁: mean FEV₁ % predicted Follow‐up: 15 months		FEV₁ % predicted was 84.11% after treatment with oral ciprofloxacin.	FEV₁ % predicted in the IV ceftazidime group was 2.08 % higher (0.81% lower to 4.97% higher).	N/A	285 (1 RCT)	⊕⊕⊕⊕ high^a
FVC: mean FVC % predicted Follow‐up: 15 months		FVC % predicted was 90.94% after treatment with oral ciprofloxacin.	FVC % predicted was 3.14% higher in the IV ceftazidime group (0.31% higher to 5.97% higher).	N/A	285 (1 RCT)	⊕⊕⊕⊕ high^a
Growth and nutritional status: weight‐for‐age z score Follow‐up: 15 months		Weight‐for‐age z score was 0.13 in the oral ciprofloxacin group.	Weight‐for‐age z score was 0.02 lower in the IV ceftazidime group (0.15 lower to 0.11 higher).	N/A	285 (1 RCT)	⊕⊕⊕⊕ high^a
Frequency of infective pulmonary exacerbations: number of participants experiencing an exacerbation Follow‐up: 15 months		356 per 1000	278 per 1000 (196 to 392 per 1000)	RR 0.78 (0.55 to 1.10)	285 (1 RCT)	⊕⊕⊕⊕ high^a
Isolation of other micro‐organisms from the respiratory tract: number of participants isolating other micro‐organisms within the 15‐month follow‐up. Follow‐up: 15 months		There was no difference between treatments in the number of participants who grew other organisms: MRSA (RR 2.07, 95% CI 0.39 to 11.14); B cepacia (RR 0.51, 95% CI 0.10 to 2.76); Candida spp (RR 1.04, 95% CI 0.78 to 1.40); and Aspergillus spp (RR 0.72, 95% CI 0.38 to 1.37).			285 (1 RCT)	⊕⊕⊕⊕ high^a
Adverse effects of antibiotics: Follow‐up: 15 months		There was no difference in serious adverse events (RR 0.97, 95% CI 0.43 to 2.16) or non‐serious adverse events (RR 0.97, 95% CI 0.75 to 1.24) between groups, except for URTI where there were fewer incidences in the oral antibiotic treatment group (RR 6.37, 95% CI 1.44 to 28.21).			285 (1 RCT)	⊕⊕⊕⊝ moderate^b
The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). B cepacia: Burkholderia cepacia; CI: confidence interval; FEV₁: forced expiratory volume in one second; FVC: forced vital capacity; IV: intravenous; MD: mean difference; MRSA: methicillin‐resistant Staphylococcus aureus; N/A: not applicable; NR: not reported; P aeruginosa: Pseudomonas aeruginosa*; RCT: randomised controlled trial; RR: risk ratio; URTI: upper respiratory tract infection.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aWe have not downgraded the evidence for this outcome despite the trial being open‐label. It is unlikely that knowledge of the allocation would influence the results for this outcome. ^bDowngraded once due to risk of bias; this was an open‐label trial, and it is unclear whether knowledge of treatment arm may have affected this outcome.

Summary of findings 10. Intravenous ceftazidime with tobramycin compared with oral ciprofloxacin

Comparison 1. Inhaled tobramycin (TNS) versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Positive respiratory culture for P aeruginosa (300 mg 2x daily) Show forest plot	2		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1.1 At 1 month	2	72	Odds Ratio (M‐H, Fixed, 95% CI)	0.04 [0.01, 0.15]
1.1.2 At 2 months	1	21	Odds Ratio (M‐H, Fixed, 95% CI)	0.21 [0.03, 1.47]
1.2 Positive respiratory culture for P aeruginosa (80 mg 2x daily) Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.2.1 At 1 month	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.2.2 At 2 months	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.2.3 At 3 months	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.2.4 At 6 months	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.2.5 At 12 months	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.3 Positive respiratory culture for P aeruginosa (combined available case analysis) Show forest plot	3		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.3.1 At 1 month	3	89	Odds Ratio (M‐H, Fixed, 95% CI)	0.06 [0.02, 0.18]
1.3.2 At 2 months	2	38	Odds Ratio (M‐H, Fixed, 95% CI)	0.15 [0.03, 0.65]
1.4 Positive respiratory culture for P aeruginosa (combined) ‐ best case Show forest plot	3		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.4.1 At 1 month	3	90	Odds Ratio (M‐H, Fixed, 95% CI)	0.06 [0.02, 0.17]
1.4.2 At 2 months	2	39	Odds Ratio (M‐H, Fixed, 95% CI)	0.14 [0.03, 0.60]
1.4.3 At 3 months	1	18	Odds Ratio (M‐H, Fixed, 95% CI)	0.14 [0.02, 1.16]
1.4.4 At 6 months	1	18	Odds Ratio (M‐H, Fixed, 95% CI)	0.04 [0.00, 0.48]
1.4.5 At 12 months	1	18	Odds Ratio (M‐H, Fixed, 95% CI)	0.01 [0.00, 0.26]
1.5 Positive respiratory culture for P aeruginosa (combined) ‐ worst case Show forest plot	3		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.5.1 At 1 month	3	90	Odds Ratio (M‐H, Fixed, 95% CI)	0.07 [0.02, 0.19]
1.5.2 At 2 months	2	39	Odds Ratio (M‐H, Fixed, 95% CI)	0.18 [0.04, 0.73]
1.5.3 At 3 months	1	18	Odds Ratio (M‐H, Fixed, 95% CI)	0.36 [0.05, 2.77]
1.5.4 At 6 months	1	18	Odds Ratio (M‐H, Fixed, 95% CI)	0.16 [0.01, 1.83]
1.5.5 At 12 months	1	18	Odds Ratio (M‐H, Fixed, 95% CI)	0.36 [0.05, 2.77]
1.6 Weight (kg) ‐ change from baseline Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.6.1 At 1 month	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.6.2 At 2 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.7 Adverse events Show forest plot	2		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.7.1 Cough	2	72	Odds Ratio (M‐H, Fixed, 95% CI)	0.76 [0.10, 5.77]
1.8 Modified Shwachmann score ‐ change from baseline Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.8.1 At 1 month	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.8.2 At 2 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 1. Inhaled tobramycin (TNS) versus placebo

Comparison 2. Inhaled tobramycin (TNS) 28 days versus 56 days

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Time to next isolation of P aeruginosa from BAL, sputum or oropharyngeal cultures Show forest plot	1		Hazard Ratio (IV, Fixed, 95% CI)	Totals not selected

2.2 Number of respiratory exacerbations Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2.2.1 Until recurrence of P. aeruginosa	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3 Adverse events (up to 3 months) Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2.3.1 Cough	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.2 Productive cough	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.3 Haemoptysis	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.4 Rhinitis	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.5 Sinusitis	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.6 Nasopharyngitis	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.7 Tonsilitis	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.8 Oropharyngeal pain	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.9 Dysphonia	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.10 Headache	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.11 URTI	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.12 Lung disorder	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.13 Bronchitis	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.14 P. aeruginosa infection	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.15 Influenza	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.16 Otitis media	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.17 Deafness	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.18 Drug level increased	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.19 Pyrexia	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.20 Vomiting	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.21 Varicella	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4 Adverse events (over 3 months) Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2.4.1 Cough	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.2 Productive cough	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.3 Haemoptysis	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.4 Rhinitis	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.5 Sinusitis	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.6 Nasopharyngitis	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.7 Tonsilitis	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.8 Oropharyngeal pain	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.9 Dysphonia	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.10 Headache	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.11 URTI	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.12 Lung disorder	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.13 Bronchitis	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.14 P. aeruginosa infection	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.15 Influenza	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.16 Otitis media	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.17 Deafness	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.18 Drug level increased	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.19 Pyrexia	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.20 Vomiting	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.21 Varicella	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 2. Inhaled tobramycin (TNS) 28 days versus 56 days

Comparison 3. Cycled inhaled tobramycin (TNS) versus culture‐based TNS

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Participants with one or more isolates of P aeruginosa from respiratory tract Show forest plot	1		Odds Ratio (IV, Fixed, 95% CI)	Totals not selected

3.2 FEV₁ % predicted ‐ change from baseline Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

3.2.1 Mean duration of 70 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.3 Weight (kg) ‐ change from baseline Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

3.3.1 Mean duration of 70 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.4 Height (cm) ‐ change from baseline Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

3.4.1 Mean duration of 70 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.5 Time to severe pulmonary exacerbation Show forest plot	1		Hazard Ratio (IV, Fixed, 95% CI)	Totals not selected

3.6 Participants with one or more severe pulmonary exacerbations Show forest plot	1		Odds Ratio (IV, Fixed, 95% CI)	Totals not selected

3.7 Time to pulmonary exacerbation (any severity) Show forest plot	1		Hazard Ratio (IV, Fixed, 95% CI)	Totals not selected

3.8 Participants with one or more pulmonary exacerbations (any severity) Show forest plot	1		Odds Ratio (IV, Fixed, 95% CI)	Totals not selected

3.9 Participants with new isolates of Stenotrophomonas maltophilia Show forest plot	1		Odds Ratio (IV, Fixed, 95% CI)	Totals not selected

3.10 Participants with one or more serious adverse event Show forest plot	1		Odds Ratio (IV, Fixed, 95% CI)	Totals not selected

Comparison 3. Cycled inhaled tobramycin (TNS) versus culture‐based TNS

Comparison 4. Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin (TNS)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Participants with one or more isolates of P aeruginosa from respiratory tract Show forest plot	1		Odds Ratio (IV, Fixed, 95% CI)	Totals not selected

4.2 FEV₁ % predicted ‐ change from baseline Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

4.2.1 Mean duration of 70 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.3 Weight (kg) ‐ change from baseline Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

4.3.1 Mean duration of 70 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.4 Height (cm) ‐ change from baseline Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

4.4.1 Mean duration of 70 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.5 Time to severe pulmonary exacerbation Show forest plot	1		Hazard Ratio (IV, Fixed, 95% CI)	Totals not selected

4.6 Participants with one or more severe pulmonary exacerbations Show forest plot	1		Odds Ratio (IV, Fixed, 95% CI)	Totals not selected

4.7 Time to pulmonary exacerbation (any severity) Show forest plot	1		Hazard Ratio (IV, Fixed, 95% CI)	Totals not selected

4.8 Participants with one of more pulmonary exacerbation (any severity) Show forest plot	1		Odds Ratio (IV, Fixed, 95% CI)	Totals not selected

4.9 Participants with new isolates of Stenotrophomonas maltophilia Show forest plot	1		Odds Ratio (IV, Fixed, 95% CI)	Totals not selected

4.10 Participants with one or more serious adverse event Show forest plot	1		Odds Ratio (IV, Fixed, 95% CI)	Totals not selected

Comparison 4. Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin (TNS)

Comparison 5. Oral ciprofloxacin and inhaled colistin versus inhaled tobramycin (TNS)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Positive respiratory culture for P aeruginosa Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5.1.1 In first 6 months	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5.1.2 At 24 months	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5.2 Adverse events Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5.2.1 Severe cough	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 5. Oral ciprofloxacin and inhaled colistin versus inhaled tobramycin (TNS)

Comparison 6. Inhaled colistin plus oral ciprofloxacin versus inhaled tobramycin (TNS) plus oral ciprofloxacin

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Positive respiratory culture for P aeruginosa Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

6.1.1 In first 6 months	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.1.2 At end of follow‐up (median 16 months)	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.2 FEV₁ % predicted (relative change from baseline) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

6.2.1 At mean 54 days	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
6.3 Microbiology status (post‐trial) Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

6.3.1 Stenotrophomonas maltophilia	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.3.2 Achromobacter xylosoxidans	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.3.3 Aspergillus species	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.4 Adverse events leading to trial discontinuation Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

6.4.1 Vomiting	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.4.2 Photosensitivity	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.4.3 Wheeze	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.4.4 Pulmonary exacerbation during early eradication treatment	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.4.5 Lack of compliance	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 6. Inhaled colistin plus oral ciprofloxacin versus inhaled tobramycin (TNS) plus oral ciprofloxacin

Comparison 7. Inhaled tobramycin (TNS) plus oral azithromycin versus TNS plus oral placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Eradication of PA after first treatment quarter Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

7.2 Number of participants experiencing an exacerbation Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

7.2.1 At 18 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.3 Number of participants requiring additional antibiotics during the study Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

7.3.1 IV antibiotics	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.3.2 Inhaled antibiotics	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.3.3 Oral antibiotics	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.4 Number of hospitalisations Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

7.5 Isolation of other micro‐organisms at any time point post‐baseline Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

7.5.1 MRSA	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.5.2 B cepacia	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.5.3 A xylosoxidans	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.5.4 S maltophilia	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.5.5 H influenzae	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.5.6 NTM	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.6 Adverse events Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

7.6.1 Any adverse event during the study	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.6.2 Serious adverse events ‐ GI disorders (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.6.3 Serious adverse events ‐ general disorders and administration site conditions	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.6.4 Serious adverse events ‐ metabolism and nutrition disorders	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.6.5 Serious adverse events ‐ infections and infestations	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.6.6 Serious adverse events ‐ nervous system disorders	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.6.7 Serious adverse events ‐ renal and urinary disorders	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.6.8 Serious adverse events ‐ respiratory, thoracic, and mediastinal disorders	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 7. Inhaled tobramycin (TNS) plus oral azithromycin versus TNS plus oral placebo

Comparison 8. Oral ciprofloxacin and inhaled colistin versus no treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Proportion colonised with P aeruginosa Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

8.1.1 At 3 months	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
8.1.2 At 6 months	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
8.1.3 At 12 months	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
8.1.4 At 24 months	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 8. Oral ciprofloxacin and inhaled colistin versus no treatment

Comparison 9. AZLI 14 days plus placebo 14 days versus AZLI 28 days

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 Proportion of participants with negative cultures at 28 days Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

9.2 Adverse Events Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 9. AZLI 14 days plus placebo 14 days versus AZLI 28 days

Comparison 10. IV ceftazidime with tobramycin versus oral ciprofloxacin

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 Eradication of P aeruginosa from respiratory samples at 3 months and remaining free Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

10.1.1 At 15 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.2 FEV₁ % predicted Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

10.2.1 At 15 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10.3 FVC % predicted Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

10.3.1 At 15 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10.4 FEF_25-75 Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

10.4.1 At 15 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10.5 Growth and nutritional status: height‐for‐age z score Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

10.5.1 At 15 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10.6 Growth and nutritional status: weight‐for‐age z score Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

10.6.1 At 15 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10.7 Growth and nutritional status: BMI z score (paediatric) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

10.7.1 At 15 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10.8 Growth and nutritional status: BMI (kg/m²; adult) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

10.8.1 At 15 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10.9 Frequency of exacerbations: number of participants who experienced an exacerbation Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

10.9.1 At 15 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.10 Frequency of exacerbations: number of participants admitted to hospital Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

10.11 Isolation of other organisms: number of participants isolating a positive culture during 15‐month study period Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

10.11.1 MRSA	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.11.2 B cepacia	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.11.3 Candida spp	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.11.4 Aspergillus spp	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12 Adverse events Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

10.12.1 Any non‐serious adverse event (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.2 Non‐serious adverse events: cough (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.3 Non‐serious adverse events: URTI (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.4 Non‐serious adverse events: productive cough (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.5 Serious adverse events (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.6 Serious adverse events: GI disorders (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.7 Serious adverse events: general disorders and administration site conditions (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.8 Serious adverse events: Hepatobiliary disorders (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.9 Serious adverse events: Infections and infestations (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.10 Serious adverse events: nervous system disorders (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.11 Serious adverse events: psychiatric disorders (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.12 Serious adverse events: renal and urinary disorders (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.13 Serious adverse events: respiratory, thoracic and mediastinal disorders (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.14 Serious adverse events: skin and subcutaneous tissue disorders (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.15 Serious adverse events: surgical and medical procedures (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.16 Serious adverse events: vascular disorders (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 10. IV ceftazidime with tobramycin versus oral ciprofloxacin